U.S. patent application number 15/265415 was filed with the patent office on 2017-07-06 for method of treatment of schizophreniform disorder.
The applicant listed for this patent is CUREMARK, LLC. Invention is credited to James Fallon, Joan M. Fallon, Matthew Heil, James Szigethy.
Application Number | 20170189501 15/265415 |
Document ID | / |
Family ID | 47042184 |
Filed Date | 2017-07-06 |
United States Patent
Application |
20170189501 |
Kind Code |
A1 |
Fallon; Joan M. ; et
al. |
July 6, 2017 |
METHOD OF TREATMENT OF SCHIZOPHRENIFORM DISORDER
Abstract
Described herein are compositions which include digestive
enzymes and which are formulated to reduce one or more symptoms of
a neuropsychiatric disorder. Also described herein is a method for
treating an individual with a neuropsychiatric disorder using
digestive enzymes and their derivatives to alleviate the symptoms
of neuropsychiatric disorders. The method comprises administering
to the individual an effective amount of digestive enzymes that are
either naturally or recombinantly derived, or their derivatives, in
an amount effective to reduce one or more symptoms of the
neuropsychiatric disorder.
Inventors: |
Fallon; Joan M.;
(Bronxville, NY) ; Heil; Matthew; (Sherman,
CT) ; Szigethy; James; (Montgomery, NY) ;
Fallon; James; (Armonk, NY) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
CUREMARK, LLC |
Rye |
NY |
US |
|
|
Family ID: |
47042184 |
Appl. No.: |
15/265415 |
Filed: |
September 14, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14612604 |
Feb 3, 2015 |
9492515 |
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15265415 |
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14007793 |
Dec 27, 2013 |
8980252 |
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PCT/US12/34489 |
Apr 20, 2012 |
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14612604 |
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61477988 |
Apr 21, 2011 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 25/00 20180101;
A61K 45/06 20130101; C12Y 301/01 20130101; A61K 38/47 20130101;
A61K 38/54 20130101; C12Y 304/00 20130101; A61K 9/0053 20130101;
A61K 38/465 20130101; A61K 38/48 20130101; C12Y 302/01
20130101 |
International
Class: |
A61K 38/54 20060101
A61K038/54; A61K 9/00 20060101 A61K009/00 |
Claims
1-32. (canceled)
33. A composition that comprises digestive enzymes, for use in the
prevention or treatment of one or more symptoms of a
neuropsychiatric disorder.
34-99. (canceled)
100. A method for treating a schizophreniform disorder in a subject
having a schizophreniform disorder, comprising orally administering
to the subject a dose of a therapeutically effective amount of a
pharmaceutical composition that comprises digestive enzymes,
wherein the digestive enzymes comprise a protease, an amylase, and
a lipase; and wherein the dose of the pharmaceutical composition
comprises from 55,000 to 310,000 units of protease activity,
whereby the schizophreniform disorder is treated.
101. The method of claim 100, wherein the pharmaceutical
composition is a dosage formulation selected from the group
consisting of a pill, a tablet, a capsule, a microcapsule, a
mini-capsule, a time-release capsule, a mini-tab, a sprinkle, and a
combination thereof.
102. The method of claim 100, wherein the pharmaceutical
composition comprises amounts of the protease and the lipase in
U.S.P. units/dose in a ratio from about 1:1 to about 20:1 of the
protease to the lipase; and amounts of the protease and the amylase
(in U.S.P. units/dose) in a ratio from about 1:0.1 to about 1:10 of
the protease to the amylase.
103. The method of claim 100, wherein the pharmaceutical
composition comprises amounts of the protease and the lipase in
U.S.P. units/dose in a ratio from about 4:1 to about 10:1 of the
protease to the lipase.
104. The method of claim 100, wherein the pharmaceutical
composition comprises amounts of the protease and the lipase in
U.S.P units/dose in a ratio of about 6:1.
105. The method of claim 100, wherein the pharmaceutical
composition comprises amounts of the protease and the lipase in
U.S.P. units/dose in a ratio of about 1:1.
106. The method of claim 100, wherein the pharmaceutical
composition further comprises a coating.
107. The method of claim 106, wherein the coating is a lipid
coating.
108. The method of claim 100, wherein the pharmaceutical
composition is manufactured using a technology selected from the
group consisting of enteric coating, lipid encapsulation, direct
compression, dry granulation, wet granulation, and a combination
thereof.
109. The method of claim 100, wherein the pharmaceutical
composition is administered 1, 2, 3 or 4 times daily.
110. The method of claim 100, wherein the pharmaceutical
composition is administered 1, 2, 3 or 4 times weekly.
111. The method of claim 100, wherein the digestive enzymes are
animal enzymes, plant enzymes, synthetic enzymes, or a combination
thereof.
112. The method of claim 111, wherein digestive enzymes are animal
enzymes that are derived from a mammal.
113. The method of claim 112, wherein the mammal is a pig.
114. The method of claim 111, wherein digestive enzymes are animal
enzymes that are derived from a pancreas.
115. A method for treating one or more positive symptoms of a
schizophreniform disorder in a subject having a schizophreniform
disorder, comprising administering to the subject a therapeutically
effective amount of a pharmaceutical composition that comprises
digestive enzymes; wherein the digestive enzymes comprise a
protease, an amylase and a lipase, whereby the one or more positive
symptoms of the schizophreniform disorder are treated.
116. The method of claim 115, wherein the one or more positive
symptoms of the schizophreniform disorder comprise hallucinations,
delusions, disorganized thought, disorganized speech, movement
disorders, bizarre behavior, or a combination thereof.
117. A method for treating one or more negative symptoms of a
schizophreniform disorder in a subject having a schizophreniform
disorder, comprising administering to the subject a therapeutically
effective amount of a pharmaceutical composition that comprises
digestive enzymes; wherein the digestive enzymes comprise a
protease, an amylase and a lipase, whereby the one or more negative
symptoms of the schizophreniform disorder are treated.
118. The method of claim 117, wherein the one or more negative
symptoms of the schizophreniform disorder comprise loss of
motivation, restricted range of emotional experience and
expression, reduced hedonic capacity, affective flattening, alogia,
avolition, or a combination thereof.
119. A method for treating one or more symptoms of cognitive
impairment of a schizophreniform disorder in a subject having a
schizophreniform disorder, comprising administering to the subject
a therapeutically effective amount of a pharmaceutical composition
that comprises digestive enzymes; wherein the digestive enzymes
comprise a protease, an amylase and a lipase, whereby the one or
more symptoms of cognitive impairment of the schizophreniform
disorder are treated.
120. The method of claim 119, wherein the one or more symptoms of
cognitive impairment of the schizophreniform disorder comprise poor
executive function, inability to use learned information,
difficulty paying attention and/or focusing, or a combination
thereof.
Description
BACKGROUND OF THE INVENTION
[0001] Neuropsychiatric disorders are some of the most
debilitating, socially isolating and economically draining of all
illnesses. The manifestations of neuropsychiatric disorders, often
mistaken as willful or controllable behaviors cause the illness to
be misdiagnosed and thus poorly treated. Most treatments for
neuropsychiatric disorders have severe and devastating side
effects. These side effects will often discourage the patient from
continuing treatment and are often the cause of relapse.
[0002] Psychotic disorders represent the most difficult of all
neuropsychiatric disorders to control. The invariate nature of the
presentation of symptoms of these disorders, together with the side
effects exhibited by medications used to alleviate these symptoms,
makes their treatment difficult.
[0003] The introduction of antipsychotic drugs in the 1950's
heralded the "golden age" of psychopharmacology. Their development
has been compared to the discovery of antibiotics for infectious
diseases. Conventional or "typical" antipsychotic drugs, typified
by chlorpromazine and haloperidol, have a proven track record in
the treatment of schizophrenia. However, the "typical"
antipsychotics described below have substantial limitations. They
are most effective against the psychotic symptoms of the illness in
its early stages, but their side effects are troubling and
contribute significantly to non-compliance, which leads to relapse
and re-hospitalization.
SUMMARY OF THE INVENTION
[0004] There is a growing belief among clinicians that the
"atypical" antipsychotics are or should become first-line
treatments in schizophrenia. However, the exact nature and extent
of the clinical advantages of the atypical drugs are not known.
Moreover, they may cost ten times as much as older "typical"
antipsychotics. Although a variety of claims of efficacy and safety
have been made, they are often based on insufficient evidence.
[0005] Among the reasons for this is traditional clinical trials
have excluded many patients with schizophrenia, including those who
are substance abusers, violent or uncooperative, making it
difficult to generalize the results of such studies to real world
patients. For reasons of external validity, treatment effectiveness
studies have sought to use more representative sampling techniques.
However, even effectiveness studies rarely have representative
samples of providers and systems of care, or large enough samples
to have sufficient power to examine the role of external factors
affecting treatment outcome.
[0006] There is a need for a new class of drugs to treat
neuropsychiatric disorders, with at least equal effectiveness, but
with a severely reduced side effect profile, which will enhance
compliance and lower co-morbid symptomatology.
[0007] Provided herein are compositions of digestive enzymes which
are useful in the prevention or treatment of one or more symptoms
of a neuropsychiatric disorder. Also provided herein are
compositions of digestive enzymes which are useful for use in the
prevention or treatment of one or more symptoms of schizophrenia.
Treatment of a neuropsychiatric disorder (e.g., schizophrenia)
encompasses stasis of one or more symptoms (i.e., they do not
worsen), as well as reduction (partial or complete) of one or more
symptoms. In one embodiment, one or more symptoms of such disorders
are reduced in severity or duration by about 2%, about 5%, about
10%, about 15%, about 20%, about 25%, about 30%, about 35%, about
40%, about 45%, about 50%, about 55%, about 60%, about 65%, about
70%, about 75%, about 80%, about 90%, about 95%, or about 100%. In
another embodiment, one or more symptoms of such disorders are
reduced in severity or duration by about 2-fold, about 5-fold,
about 10-fold, about 15-fold, about 20-fold, about 25-fold, about
30-fold, about 35-fold, about 40-fold, about 45-fold, about
50-fold, about 55-fold, about 60-fold, about 65-fold, about
70-fold, about 75-fold, about 80-fold, about 90-fold, about
95-fold, about 100-fold or more. Compositions may include not only
one or more digestive enzymes, but also one or more
pharmaceutically acceptable carriers, excipients, buffers, fillers,
binders, stabilizers, surfactants, diluents, taste maskers,
etc.
[0008] Provided herein is a method for using digestive enzymes and
their derivatives to alleviate one or more symptoms of
neuropsychiatric disorders. The method comprises administering to
the individual one or more digestive enzymes that are either
naturally- or recombinantly-derived, or their derivatives, in an
amount effective to reduce the one or more symptoms of the
neuropsychiatric disorder. Digestive enzymes generally comprise all
proteases, amylases, and lipases, as well as other proteins
secreted in a mammal that affect the digestive process either
directly or indirectly.
[0009] The disorders that present symptoms potentially suitable for
alleviation according to the present method include, but are not
limited to: Adjustment disorders, addiction, Alzheimer's disease,
Anxiety disorders, Bipolar disorder, cognitive disorders,
dementias, Dissociative disorders, eating disorders,
Impulse-control disorders, Mood disorders, Sexual disorders, sleep
disorders, psychotic disorders such as schizophrenic disorders,
Somatoform disorders, substance abuse disorders and personality
disorders. In one embodiment, a schizophreniform disorder (e.g.,
schizophrenia) is treated according to the methods described
herein
[0010] In another aspect, this disclosure relates to a
pharmaceutical composition comprising a therapeutically effective
amount of an enzyme preparation, which comprises a core amount of
pancreatic or digestive enzymes effective for treating a subject
susceptible to treatment by the enzymes, specifically those
suffering with neuropsychiatric disorders.
[0011] In another aspect, this disclosure relates to a
pharmaceutical composition comprising a therapeutically effective
amount of an enzyme preparation, which comprises a core amount of
pancreatic or digestive enzymes effective for treating a subject
susceptible to treatment by the enzymes, specifically those
suffering with schizophrenia.
[0012] In another aspect, this disclosure relates to a
pharmaceutical composition comprising a therapeutically effective
amount of an enzyme preparation, which comprises a core amount of
pancreatic or digestive enzymes effective for treating a subject
susceptible to treatment by the enzymes, specifically those
suffering with psychosis.
[0013] In one aspect, provided herein is a method for treating an
individual exhibiting one or more symptoms of a neuropsychiatric
disorder, the method comprising administering a therapeutically
effective amount of digestive enzymes to the individual. In one
embodiment, the neuropsychiatric disorder is a schizophreniform
disorder, or a mild anxiety state.
[0014] In another embodiment, a symptom of the neuropsychiatric
disorder may be a positive symptom, a negative symptom, a symptom
of cognitive impairment, or a combination thereof. Positive
symptoms are include, but are not limited to hallucinations,
delusions, disorganized thought, disorganized speech (e.g.,
frequent derailment or incoherence), movement disorders, bizarre
behavior, and any combinations thereof. Negative symptoms include,
but are not limited to limited to loss of motivation, restricted
range of emotional experience and expression, reduced hedonic
capacity, affective flattening, alogia, avolition, and any
combinations thereof. Symptoms of cognitive impairment include, but
are not limited to poor executive function, inability to use
learned information, difficulty paying attention and/or focusing,
and any combinations thereof.
[0015] Digestive enzymes to be used in a composition described
herein include amylase, lipase, protease, and any combination
thereof. In another embodiment, digestive enzymes to be used in
such compositions may further include chymotrypsin, trypsin,
pancreatin, papain, and any combination thereof. Digestive enzymes
may be derived from a source such as, for example, animal enzymes,
plant enzymes, synthetic enzymes, and any combination thereof. In a
one embodiment, the animal enzyme is derived from a mammal.
[0016] Digestive enzymes may be manufactured using any appropriate
technology including, but not limited to, enteric coating, lipid
encapsulation, direct compression, dry granulation, wet
granulation, and any combination thereof. A preparation may be an
oral dosage formulation such as, for example, pills, tablets,
capsules, microcapsules, mini-capsules, time released capsules,
mini-tabs, sprinkles, and any combination thereof. In one
embodiment digestive enzymes are provided as a pharmaceutical
composition. In one embodiment the pharmaceutical composition is in
the form of encapsulated sprinkles. In one embodiment the
encapsulation is a lipid coating. In one embodiment the lipid
coating is a soy lipid coating.
[0017] Provided herein is a method is presented for treating a
symptom of a neuropsychiatric disorder in an individual comprising
administering an effective amount of a composition comprising one
or more digestive enzymes to the individual. In one embodiment, the
neuropsychiatric disorder is schizophrenia, schizophreniform
disorders, or mild anxiety states.
[0018] In one embodiment, the digestive enzyme is selected from the
group consisting of amylase, lipase, protease, and any combination
thereof. In another embodiment, the digestive enzyme is further
selected from the group consisting of: chymotrypsin, trypsin,
pancreatin, papain, and any combination thereof. In yet another
embodiment, the digestive enzymes are derived from a source
selected from the group consisting of animal enzymes, plant
enzymes, synthetic enzymes, and any combination thereof. In one
embodiment the digestive enzymes are pancreatic digestive enzymes.
In one embodiment, the animal enzyme is derived from a mammal. In
one embodiment the mammal is a pig. In one embodiment, digestive
enzymes are derived from a mammalian pancreas. In one embodiment
the pancreas is a pig pancreas.
[0019] In one embodiment, the total amount of protease in a
composition ranges from about 5,000 to about 1,500,000 USP
units/dose. In another embodiment, the total amount of amylase in a
composition ranges from about 1,000 to about 15,000,000 U.S.P.
units/dose. In another embodiment, the total amount of lipase in a
composition ranges from about 1,500 to about 282,000 U.S.P.
units/dose. In one embodiment a pharmaceutical composition
comprises about 23,000 U.S.P. units/dose of lipase, about 144,000
U.S.P. units/dose of amylase and about 140,000 U.S.P. units/dose of
protease. In another embodiment a pharmaceutical composition
contains 23040 U.S.P. units/dose of lipase, about 144,000 U.S.P.
units/dose of amylase and about 140,400 U.S.P. units/dose of
protease.
[0020] Provided herein are methods for preventing or treating one
or more symptoms of a neuropsychiatric disorder in an individual
comprising, administering to said individual a composition
comprising one or more digestive enzymes, wherein one or more
symptoms of said neuropsychiatric disorder are partially or
completely reduced. In one aspect, the neuropsychiatric disorder is
a schizophreniform disorder such as, for example, schizophrenia.
Symptoms of schizophrenia that may be treated with such methods
include, but are not limited to, positive symptoms, negative
symptoms, cognitive impairment, and any combination thereof.
Positive symptoms include, but are not limited to, hallucinations,
delusions, disorganized thought, disorganized speech (e.g.,
frequent derailment or incoherence), movement disorders, bizarre
behavior, and any combination thereof. Negative symptoms include,
but are not limited to, loss of motivation, restricted range of
emotional experience and expression, reduced hedonic capacity,
affective flattening, alogia, avolition, and any combination
thereof. Symptoms of cognitive impairment include, but are not
limited to, poor executive function, inability to use learned
information, difficulty paying attention and/or focusing, and any
combination thereof.
INCORPORATION BY REFERENCE
[0021] All publications and patent applications mentioned in this
specification are herein incorporated by reference to the same
extent as if each individual publication or patent application was
specifically and individually indicated to be incorporated by
reference.
BRIEF DESCRIPTION OF THE DRAWINGS
[0022] The novel features of the disclosure are set forth with
particularity in the appended claims. A better understanding of the
features and advantages of the present disclosure will be obtained
by reference to the following detailed description that sets forth
illustrative embodiments, in which the principles of the disclosure
are utilized, and the accompanying drawings.
[0023] FIG. 1. The Test Substances.
[0024] FIG. 2. Description of the Dosages.
[0025] FIG. 3. Description of the Enzyme Components.
[0026] FIG. 4. Distance Moved by ckr Mice Treated with CM100 in
Spontaneous Open Field Assays.
[0027] FIG. 5. Velocity of ckr Mice Treated with CM100 in
Spontaneous Open Field Assays.
[0028] FIG. 6. Aripiprazole Dose Dependent Response in ckr
Mice.
[0029] FIG. 7. Total distance moved in the 90 min recording of
spontaneous open field test on male B6 mice. Data plot as
Mean.+-.SEM. Pair-wise comparison using Student's t-test.
.alpha.=0.05. *, p<0.05; **, p<0.01; ***, p<0.001; N.S.,
not significant.
[0030] FIG. 8. Velocity in the 90 min recording of spontaneous open
field test on male B6 mice. Data plot as Mean.+-.SEM. Pair-wise
comparison using Student's t-test. .alpha.=0.05. *, p<0.05; **,
p<0.01; ***, p<0.001; N.S., not significant.
DETAILED DESCRIPTION OF THE INVENTION
[0031] Provided herein are methods of treating disorders relating
to neuropsychiatric disorders and methods of diagnosing the
likelihood of having or developing a neuropsychiatric disorder.
[0032] Antipsychotic drugs are divided into two categories:
"typical" antipsychotics and the newer "atypical" antipsychotics.
Typical antipsychotics have been shunned in recent times due to
their side effect profile which includes the production of
extrapyramidal symptoms such a facial tics, gait disturbances,
proprioceptive difficulties, rigidity, persistent muscle spasms,
shakiness, restlessness, jitteriness and uncharacteristic
movements.
[0033] Examples of antipsychotic drugs which fall into the
"typical" category are: chlorpromazine, fluphenazine, haloperidol,
loxapine, mesoridazine, molindone, perphenazine, pimozide,
prochlorperazine, thiothixene, thioridazine and
trifluoperazine.
[0034] With the advent of atypical antipsychotic drugs and their
potential for enhanced efficacy and safety, the risk/benefit
profile of this drug class has changed. Following the
re-introduction of the first atypical antipsychotic, clozapine, in
1990, several new atypical drugs have become available for clinical
use and now comprise more than 50% of the antipsychotic drug market
in the United States. These drugs include risperidone (1994),
olanzapine (1996) and quetiapine (1997).
[0035] Examples of "atypical" antipsychotic drugs are:
aripiprazole, asenapine, clozapine, iloperidone, lurasidone,
olanzapine, paliperidone, quetiapine, risperidone and ziprasidone
among others.
[0036] Recent research has provided strong evidence of the efficacy
of atypicals in schizophrenia, and demonstrated that they greatly
reduce the risk of extrapyramidal side effects, as well as reducing
tardive dyskinesias. "Dyskinesias" are repetitive, uncontrollable
and purposeless movements of the body or face. "Tardive" refers to
those symptoms that develop after long-term antipsychotic treatment
(several years). Unlike early dyskinesia symptoms, tardive
dyskinesias may become permanent even if the antipsychotic
medication is stopped.
[0037] These "atypical" antipsychotics are not without their side
effects. While they have largely replaced the older medications,
atypicals are rather expensive and carry a significant risk of
weight gain (sometimes extreme weight gain) and diabetes. However,
they may be more effective than the "typical" antipsychotics for
such conditions as schizophrenia, and other schizoaffective
disorders as well as for multiple types of depression and other
mental illnesses.
[0038] Although the antipsychotics were first developed for
schizophrenia, antipsychotic drugs are now broadly used for other
disorders, including behavioral signs and symptoms associated with
Alzheimer's disease, dementias, depression, and are generally
applied to the entire classes of neuropsychiatric disorders
including: Adjustment disorders, Anxiety disorders, Dissociative
disorders, Eating disorders, Impulse-control disorders, Mood
disorders, Sexual disorders, Sleep disorders, psychotic disorders,
Sexual disorders, Somatoform disorders, Substance abuse disorders,
and Personality disorders. Despite their widespread use in these
conditions, the overall effectiveness and safety of these drugs
remain unclear.
Neurological and Neuropsychiatric Disorders
[0039] In accordance with the present disclosure, a method is
presented for alleviating symptoms of neurological disorders. In
one embodiment, the method comprises administering to an individual
a digestive enzyme either naturally or recombinantly derived, or
their derivatives in an amount effective to reduce the symptoms of
the neurological disorders.
[0040] There are over 300 neuropsychiatric disorders listed in the
DSM-IV and there is overlap among the different diagnoses.
Neuropsychiatric disorders are categorized according to their
predominant features. For example, phobias, social anxiety and
post-traumatic stress disorder all include anxiety as a main
feature of the disorder. Schizophrenia and related disorders such
as delusional disorder, brief psychotic disorder, schizoaffective
disorder, schizophreniform disorder and shared psychotic disorder
(a disorder that is characterized by the individual's inability to
determine real from unreal), share similar characteristics.
[0041] In one embodiment, the neurological disorders that present
symptoms potentially suitable for alleviation according to the
present method include, but are not limited to the following
disorders and categories of disorders: Adjustment disorders,
addiction, Alzheimer's disease, Anxiety disorders, Bipolar
disorder, cognitive disorders, dementias, Dissociative disorders,
eating disorders, Impulse-control disorders, Mood disorders, Sexual
disorders, sleep disorders, psychotic disorders such as
schizophrenic disorders (e.g., schizophrenia), Somatoform
disorders, substance abuse disorders and personality disorders.
[0042] As used herein, a schizophreniform disorder, refers to a
psychotic disorder characterized by distortions of reality and
disturbances of thought and language and withdrawal from social
contact.
[0043] Examples of anxiety conditions which are treated using the
method of this disclosure include but are not limited to anxiety
disorders, panic disorder, panic disorder with agoraphobia, panic
disorder without agoraphobia, agoraphobia without history of panic
disorders, social phobia, simple phobia, obsessive compulsive
disorder, post-traumatic stress disorder, generalized anxiety
disorder, anxiety disorder--not otherwise specified (NOS), organic
anxiety disorder, psychoactive substance anxiety disorder,
separation anxiety disorder, avoidant disorder of childhood or
adolescence, and overanxious disorder.
[0044] Examples of neuropsychiatric conditions which are treated
using the method of this disclosure include, but are not limited
to, schizophrenia, catatonic, subchronic; schizophrenia, catatonic,
chronic; schizophrenia, catatonic, subchronic with acute
exacerbation; schizophrenia, catatonic, chronic with acute
exacerbation; schizophrenia, catatonic, in remission;
schizophrenia, catatonic, unspecified; schizophrenia, disorganized,
subchronic; schizophrenia, disorganized, chronic; schizophrenia,
disorganized, subchronic with acute exacerbation; schizophrenia,
disorganized, chronic with acute exacerbation; schizophrenia,
disorganized, in remission; schizophrenia, disorganized,
unspecified schizophrenia, paranoid, subchronic; schizophrenia,
paranoid, chronic; schizophrenia, paranoid, subchronic with acute
exacerbation; schizophrenia, paranoid, chronic with acute
exacerbation; schizophrenia, paranoid, in remission; schizophrenia,
paranoid, unspecified; schizophrenia, undifferentiated, subchronic;
schizophrenia, undifferentiated, chronic; schizophrenia,
undifferentiated, subchronic with acute exacerbation;
schizophrenia, undifferentiated, chronic with acute exacerbation;
schizophrenia, undifferentiated, in remission; schizophrenia,
undifferentiated, unspecified; schizophrenia, residual, subchronic;
schizophrenia, residual, chronic; schizophrenia, residual,
subchronic with acute exacerbation; schizophrenia, residual,
chronic with acute exacerbation; schizophrenia, residual, in
remission; schizophrenia, residual, unspecified; delusional
(paranoid) disorder; brief reactive psychosis; schizophreniform
disorder; schizoaffective disorder; personality disorders,
schizoid; and personality disorders, schizotypal. In one
embodiment, clinical features or symptoms of schizophrenia include
positive symptoms, which include but are not limited to psychosis,
hallucinations, delusions, disorganized thought, disorganized
speech (e.g., frequent derailment or incoherence), movement
disorders, and bizarre behavior. Delusions include but are not
limited to false beliefs that significantly hinder a person's
ability to function. For example, an individual may have the
delusion that people are trying to hurt them when there is no
evidence of this, or the individual having the delusion that they
are somebody else. Hallucinations include false perceptions.
Hallucinations may be visual (e.g., seeing things that are not
there), auditory (e.g., hearing things that are not there),
olfactory (e.g., smelling things that are not there), tactile
(e.g., feeling sensations on the skin that are not there, such as
the feeling of bugs crawling on the skin), or gustatory. Auditory
hallucinations and paranoia about others reading their minds, or
being able to be in their bodies are examples of symptoms
experienced by schizophrenics. These symptoms appear to express an
excess or distortion of normal function. Psychosis as used herein
generally refers to an abnormal condition of the mind, and is a
term for a mental state that may be described as a "loss of contact
with reality" that is observed, in some cases, in patients with
schizophrenia. Psychosis is given to the more severe forms of
psychiatric disorder, during which hallucinations and delusions and
impaired insight may occur.
[0045] In another embodiment, clinical features or symptoms of
schizophrenia include negative symptoms, which include but are not
limited to loss of motivation, restricted range of emotional
experience and expression, reduced hedonic capacity, affective
flattening, alogia, and avolition. Negative symptoms such as "flat
affect", lack of enjoyment, restricted communication and inability
to follow through on planned activities, losing interest in
everyday activities such as bathing, grooming, or getting dressed;
feeling out of touch with other people, family, or friends; a lack
of feeling or emotion (apathy); having little emotion or
inappropriate feelings in certain situations; and having less
ability to experience pleasure may be experienced. These reflect
symptoms that appear to express a loss or diminution of normal
function.
[0046] In yet another embodiment, clinical features or symptoms of
schizophrenia include one or more symptoms of cognitive impairment.
For example, cognitive impairment symptoms include poor executive
function, inability to use learned information, and difficulty
paying attention and/or focusing.
[0047] Individuals with neuropsychiatric disorders frequently
exhibit one or more characteristics of the particular disorder.
Additionally, these characteristics often overlap with symptoms of
other disorders within the category of neurological disorders as
well as other disorders characterized as mental illness such as,
but not limited to, Alzheimer's and bipolar disorder. The present
disclosure contemplates that one or more symptoms as well as a
complete constellation of symptoms within one individual may be
alleviated by the present method.
[0048] Recognition and determination of a reduction in symptoms of
any and all of these disorders can be readily performed by those
skilled in the art. One will recognize that these psychotic
conditions are characterized by hallucinations, delusions or
grossly disorganized behavior, which indicates that the patient
suffers from gross impairment in reality.
[0049] In another embodiment, a patient treated with such methods
exhibits an improvement in one or more symptoms of at least about
5%, about 10%, about 15%, about 20%, about 25%, about 30%, about
35%, about 40%, about 45%, about 50%, about 55%, about 60%, about
65%, about 70%, about 75%, about 80%, about 85%, about 90%, about
95% or about 100% compared to a patient treated with a control
substance.
[0050] A "patient" to be treated by a method described herein
refers to an adult or a child. In one embodiment, a patient to be
treated is a human from about 2 and about 10 years of age, from
about 11 to about 20 years of age, or from about 21 to about 30
years of age.
Diagnosis
[0051] The recognition of the symptoms of the neuropsychiatric
disorder or disorders present in an individual and determination
that the present method may alleviate said symptoms prior to,
during, or after the practice of this method is well within the
purview of an individual ordinarily skilled in the art, who can
perform suitable clinical, diagnostic, and or observational or
other techniques required.
[0052] The DSM IV Diagnostic Criteria for Schizophrenia is
described below:
[0053] A. Characteristic Symptoms:
[0054] Two (or more) of the following, each present for a
significant portion of time during a 1-month period (or less if
successfully treated): delusions, hallucinations, disorganized
speech (e.g., frequent derailment or incoherence), grossly
disorganized or catatonic behavior, negative symptoms, i.e.,
affective flattening, alogia, or avolition. Only one Criterion A
symptom is required if delusions are bizarre or hallucinations
consist of a voice keeping up a running commentary on the person's
behavior or thoughts, or two or more voices conversing with each
other.
[0055] B. Social/Occupational Dysfunction:
[0056] For a significant portion of the time since the onset of the
disturbance, one or more major areas of functioning such as work,
interpersonal relations, or self-care are markedly below the level
achieved prior to the onset (or when the onset is in childhood or
adolescence, failure to achieve expected level of interpersonal,
academic, or occupational achievement).
[0057] C. Duration:
[0058] Continuous signs of the disturbance persist for at least 6
months. This 6-month period must include at least 1 month of
symptoms (or less if successfully treated) that meet Criterion A
(i.e., active-phase symptoms) and may include periods of prodromal
or residual symptoms. During these prodromal or residual periods,
the signs of the disturbance may be manifested by only negative
symptoms or two or more symptoms listed in Criterion A present in
an attenuated form (e.g., odd beliefs, unusual perceptual
experiences).
Compositions and Formulations
[0059] Digestive enzymes are produced by the salivary glands,
glands in the stomach, the pancreas and glands in the small
intestines. Digestive enzymes produced by the pancreas are secreted
into the duodenum, or upper segment of the small intestine, raising
the pH to around 5 or 6, and they assist in the digestion of food
components, including carbohydrates, lipids, proteins and nucleic
acids.
[0060] Digestive enzymes have been administered to mammals to treat
enzyme deficiencies caused by conditions affecting the pancreas,
such as pancreatitis and pancreatic enzyme deficiency. Pancreatic
enzymes administered to humans are commonly of porcine origin.
Individuals with cystic fibrosis require the administration of
enzymes, particularly lipases, in the maintenance of their
condition. Manufacturers of enzyme preparations for these
individuals have used enteric coatings for targeted delivery in the
distal section of the small intestine, where lipase activity is
important.
[0061] In another aspect, this disclosure relates to a
pharmaceutical composition comprising a therapeutically effective
amount of an enzyme preparation, which comprises a core amount of
pancreatic or digestive enzymes effective for treating a subject
susceptible to treatment by the enzymes, specifically those
suffering with neuropsychiatric disorders.
[0062] In another aspect, this disclosure relates to a
pharmaceutical composition comprising a therapeutically effective
amount of an enzyme preparation, which comprises a core amount of
pancreatic or digestive enzymes effective for treating a subject
susceptible to treatment by the enzymes, specifically those
suffering with schizophrenia.
[0063] In another aspect, this disclosure relates to a
pharmaceutical composition comprising a therapeutically effective
amount of an enzyme preparation, which comprises a core amount of
pancreatic or digestive enzymes effective for treating a subject
susceptible to treatment by the enzymes, specifically those
suffering with psychosis.
[0064] In one embodiment of the present disclosure, digestive
enzymes comprise proteases, amylases and lipases, as well as other
proteins secreted in a mammal that affect the digestive process
either directly or indirectly. In one aspect, digestive enzymes
present in the composition include an amylase, a protease, or a
lipase.
[0065] In another aspect, digestive enzymes present in the
composition include two or more of: an amylase, a protease, and a
lipase.
[0066] In one aspect, digestive enzymes present in the composition
include an amylase, a protease, and a lipase.
[0067] In another aspect, a composition may further contain one or
more of cellulase, papaya, bromelain, chymotrypsin, and
trypsin.
[0068] In one embodiment, the digestive or pancreatic enzyme
composition comprises one or more of the following: amylases,
proteases, cellulase, papaya, bromelain, lipases, chymotrypsin, and
trypsin.
[0069] Compositions may contain an amount of protease from about
5,000 to about 1,500,000 USP units/dose including, but not limited
to about 5,000; about 7,500; about 10,000; about 15,000; about
20,000; about 25,000; about 30,000; about 40,000; about 50,000;
about 65,000; about 75,000; about 100,000; about 140,000; about
140,400; about 150,000; about 200,000; about 250,000; about
300,000; about 350,000; about 400,000; about 450,000; about
465,000; about 500,000; about 550,000; about 600,000; about
650,000; about 700,000; about 750,000; about 800,000; about
850,000; about 900,000; about 950,000; about 1,000,000; about
1,050,000; about 1,100,000; about 1,150,000; about 1,200,000; about
1,250,000; about 1,300,000; about 1,350,000; about 1,400,000; about
1,450,000; or about 1,500,000; about 1,200,000; about 1,250,000;
about 1,300,000; about 1,350,000; about 1,400,000; about 1,450,000;
and about 1,500,000 U.S.P. units/dose along with all values in
between per dose.
[0070] Compositions may contain an amount of amylase from about
1,000 to about 15,000,000 U.S.P. units/dose including, but not
limited to about 1,000; about 3,000; about 5,000; about 7,500;
about 10,000; about 15,000; about 20,000; about 25,000; about
30,000; about 40,000; about 50,000; about 65,000; about 75,000;
about 100,000; about 144,000; about 500,000; about 1,000,000; about
2,000,000; about 3,000,000; about 4,000,000; about 5,000,000; about
6,000,000; about 7,000,000; about 8,000,000; about 9,000,000; about
10,000,000; about 11,000,000; about 12,000,000; about 13,000,000;
about 14,000,000; and about 15,000,000 U.S.P. units/dose, along
with all values in-between per dose
[0071] Compositions may contain an amount of lipase from about
1,500 to about 282,000 U.S.P. units/dose including, but not limited
to, about 1,500; about 1,880; about 2,000; about 3,000; about
5,000; about 7,500; about 10,000; about 15,000; about 20,000; about
23,000; about 23,040; about 25,000; about 30,000; about 40,000;
about 50,000; about 65,000; about 75,000; about 100,000; about
125,000; about 150,000; about 200,000; about 250,000; and about
282,000 U.S.P. units/dose along with all values in-between per
dose.
[0072] In another embodiment, the digestive enzyme composition is
comprised of protease, lipase, and amylase where the activities
are: protease between 10,000 to 1,500,000 USP units/dose including
10,000; 100,000; 150,000; 200,000; 250,000; 300,000; 350,000;
400,000; 450,000; about 465,000; 500,000; 550,000; 600,000;
650,000; 700,000; 750,000; 800,000; 850,000; 900,000; 950,000;
1,000,000; 1,050,000; 1,100,000; 1,150,000; 1,200,000; 1,250,000;
1,300,000; 1,350,000; 1,400,000; 1,450,000; and 1,500,000 along
with all values in between per dose and where the ratio of protease
to lipase is such that the amount of lipase is never more than
0.188 times the amount of protease and where the ratio of protease
activity to amylase activity is between 1:0.1 and 1:10.
[0073] In another embodiment a pharmaceutical composition comprises
about 23,000 U.S.P. units/dose of lipase, about 144,000 U.S.P.
units/dose of amylase and about 140,000 U.S.P. units/dose of
protease. In another embodiment a pharmaceutical composition
contains about 23,040 U.S.P. units/dose of lipase, about 144,000
U.S.P. units/dose of amylase and about 140,400 U.S.P. units/dose of
protease.
[0074] In some embodiments, the digestive enzyme composition
comprises at least one protease and at least one lipase, wherein
the ratio of total proteases to total lipases (in USP units) ranges
from about 5.371:1 to about 20:1 including 5.371:1, 6:1, 7:1, 8:1,
9:1, 10:1, 11;1, 12;1, 13;1, 14:1, 15:1, 16;1, 17:1, 18:1, 19:1 and
20:1, along with all values in-between. In some embodiments, the
ratio of proteases to lipases ranges from about 5.371:1 to about
10:1 including 5.371:1, 6:1, 7:1, 8:1, 9:1, and 10:1, along with
all values in-between.
[0075] In yet another embodiment, the digestive enzyme composition
comprises at least one protease and at least one lipase, wherein
the ratio of total proteases to total lipases (in USP units/dose)
ranges from about 5.371:1 to about 20:1 including 5.371:1, 6:1,
7.1, 8.1, 9:1, 10:1, 11:1, 12:1, 13:1, 14:1, 15:1, 16:1, 17:1,
18:1, 19:1, and 20:1, along with all values in-between. In another
embodiment, the digestive enzyme composition comprises at least one
protease and at least one lipase, wherein the ratio of total
proteases to total lipases (in USP units/dose) ranges from about
1:1 to about 20:1. In yet another embodiment, the ratio of
proteases to lipases ranges from about 4:1 to about 10:1. In one
embodiment, the ratio of proteases to lipases ranges from about
5.371:1 to about 10:1 including 5.371:1, 6:1, 7:1, 8:1, 9:1, and
10:1 along with all values in-between. In one embodiment, the
digestive enzyme composition comprises at least one protease and at
least one amylase, wherein the ratio of total proteases to total
amylases (in USP units/dose) ranges from about 1:0.1 to about 1:10
including 1:0.25, 1:0.5, 1:0.75, 1:1, 1:1.25, 1:1.5, 1:1.75: 1:2,
1:1.25, 1:1.5, 1:1.75, 1:1.2, 1:1.25, 1:1.5, 1:1.75, 1:1.2, 1:1.25,
1:1.5, 1:1.75, 1:1.2: 1:1.5, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1.9
and 1:10 along with all values in-between.
[0076] The disclosure also relates to a specific blend of enzymes,
with or without coating, with or without other components as
described above whereby enzyme administration occurs in individuals
with a neurological or neuropsychiatric disorder, including but not
limited to: Adjustment disorders, addiction, Alzheimer's disease,
Anxiety disorders, Bipolar disorder, cognitive disorders,
dementias, Dissociative disorders, eating disorders,
Impulse-control disorders, Mood disorders, Sexual disorders, sleep
disorders, psychotic disorders such as schizophrenic disorders
(e.g., schizophrenia), Somatoform disorders, substance abuse
disorders and personality disorders. Recognition and determination
of a reduction of symptoms of any and all of these disorders can be
readily performed by those skilled in the art using conventional
assays.
[0077] In one embodiment of the present disclosure, uncoated
digestive enzymes comprise proteases, amylases and lipases, as well
as other proteins secreted in a mammal, which affect the digestive
process either directly or indirectly. In one embodiment, the
digestive or pancreatic enzyme composition comprises one or more of
the following: amylases, proteases, cellulase, papaya, bromelain,
lipases, chymotrypsin, and trypsin.
[0078] In one embodiment the coated or uncoated digestive enzymes
to be administered are comprised of pancreatin, pancrelipase, or a
combination thereof. In one embodiment a coating technology can be
used, such as the ones described in U.S. Pat. No. 6,835,397, U.S.
RE40059, U.S. Pat. No. 6,153,236, or US 2009-0004285 which are
herein incorporated by reference in their entirety.
[0079] Enzyme preparations with non-lipid enteric coatings can be
used to deliver lipases in individuals in need of lipase
administration. Certain methods and enzyme compositions for use in
treating children and other individuals in, for example, U.S. Pat.
Nos. 7,138,123, 6,660,831, 6,632,429, 6,534,063, which is herein
incorporated by reference in its entirety.
[0080] The composition of the dosage form may include other
components, generally utilized in pharmaceutical preparations
including but not limited to binders, disintegrants, extracts,
lubricants, fillers, flavorings, preservatives, colorants, taste
maskers, diluents and coating agents, such as vegetable oil,
crystalline oils, and other coating methodologies.
[0081] In one embodiment, coating of a digestive enzyme preparation
is used to obtain release at selected transit times or in selected
locations of the gastrointestinal tract of humans. In one aspect,
this disclosure relates to controlled release enzyme preparations
administered to an individual with a neuropsychiatric disorder.
[0082] In yet another aspect, this disclosure relates to an enzyme
delivery system comprising a coated enzyme preparation having
particles which comprise: (a) a core comprising pancreatic or
digestive enzymes present in an amount from about 5% to 99% by
weight of the particles; and (b) a generally uniform coating to
provide for controlled release of the enzymes, said coating
comprising an emulsifiable lipid. In one aspect, the coated enzyme
preparation particles of the enzyme delivery system are
non-aerosolizable.
[0083] In some embodiments a coated digestive enzyme preparation
comprising (a) a core containing a digestive enzyme particle, where
the enzyme present in an amount of from about 5% to 95% by weight
of the particles, including 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%,
45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% and 95% by weight,
along with all values in-between; and (b) a coating comprising a
crystallizable lipid, wherein the coating continuously coats the
core and the crystallizable lipid releases the enzyme upon exposure
to physiological conditions.
[0084] In some embodiments a coated enzyme preparation having
particles which comprise: (a) a core comprising pancreatic or other
digestive enzymes present in an amount of from about 5% to 95% by
weight of the particles, including 5%, 10%, 15%, 20%, 25%, 30%,
35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% and 95%
by weight along with all values in-between; and (b) a generally
uniform coating to provide for controlled release of the enzymes,
the coating comprising a crystallizable lipid. In some embodiments,
the coated enzyme preparation particles of the enzyme delivery
system are non-aerosolizable.
[0085] The present disclosure also relates to methods of making the
enzyme preparations by lipid coating and/or encapsulation of
digestive enzymes. The methods comprise providing an emulsifiable
lipid, and coating pancreatic/digestive enzyme particles with the
lipid. The digestive enzymes comprise 5 to 99% of the coated enzyme
preparations by weight.
[0086] In another aspect as described herein, the inventors have
discovered that the methods of this disclosure produce coated
digestive enzyme preparations comprising digestive and/or
pancreatic enzymes coated with an emulsifiable lipid alone, or with
a lipid blend to achieve a controlled rate of enzyme release, with
increased release of the pancreatic/digestive enzyme upon exposure
of the coated preparation to a suitable solvent. The inventors have
discovered that coated pancreatic/digestive enzyme preparations
having a coating consisting essentially of one or more
monoglycerides exhibit time-sensitive biologically-suitable release
of the pancreatic/digestive enzymes upon exposure of the coated
composite to a solvent, such as water, while protecting against
release in 0.1 N HCl or acidic gastric fluid.
[0087] The nature of the human digestive tract creates challenges
for the delivery of digestive enzymes to patients susceptible to
treatment with digestive enzymes. Multiple temperature and pH
changes over the course of the digestive tract make specific
delivery a challenge but a necessity. For instance, pH as low as 1
is encountered in the stomach, but rapidly increases to a more
basic pH of 5-6 in the proximal small intestine. For example,
generally the pH in the stomach is approximately 1.2, the pH in the
duodenum is about 5.0 to 6.0; the pH in the jejunum is about 6.8,
and the pH is about 7.2 in the proximal ileum and about 7.5 in the
distal ileum. The low pH in the stomach that changes rapidly to a
more basic pH of 5-6 in the proximal small intestines calls for a
specific delivery method depending upon where the enzyme is to be
delivered.
[0088] Delivery of digestive enzymes can also be challenging due to
the rapid degradation and denaturing of enzymes at ambient room
temperature, as well as the enhanced degradation and denaturing
that can occur with high temperature, pressure, humidity and/or
exposure to light. Moisture and heat together can quickly
destabilize enzymes, reducing their effectiveness, and weaken their
potency leading to inaccurate dosing and shortened shelf life.
Denaturation or destabilization of the enzymes can reduce their
effectiveness by reducing the dose of active enzymes to less than
the amount needed for effective treatment. In one embodiment, to
protect and stabilize the pancreatic/digestive enzyme from
unfavorable conditions such as oxidation, the pancreatic/digestive
enzyme (core) is coated or encapsulated in a continuous coating
containing an emulsifiable lipid. In another aspect, this
disclosure provides new coated enzyme preparations with improved
shelf life.
[0089] Manufacturers of enzyme preparations have used enteric
coatings to deliver lipases in individuals requiring administration
of lipases, such as individuals with cystic fibrosis. Because the
porcine enzymes are delivered in a mixture of proteases, lipases
and amylases, and because these compositions for human consumption
were prepared for lipase delivery, the uses of these enteric
coatings, which include such substances as hypromellose phthalate,
dimethicone 1000, and dibutyl phthalate, preclude delivery of
proteases at the proper location for protein digestion, which is
the duodenum. All other enzyme preparations presently on the market
contain at least one of these enteric coating substances and/or
other additives in the preparation.
[0090] In one embodiment the present disclosure includes a coated
digestive enzyme preparation and/or composite, which in some
embodiments is an encapsulated pancreatic/digestive enzyme
preparation. In other aspects, the disclosure includes enzyme
delivery systems and pharmaceutical compositions comprising coated
pancreatic/digestive enzyme preparations. These coated or
encapsulated enzyme preparations contain cores comprising
pancreatic or digestive enzyme particles, and a coating comprising
an emulsifiable lipid.
[0091] The coatings in the digestive/pancreatic enzyme preparations
create a barrier to degradation and denaturation, and allow more
accurate levels of active enzymes to be utilized by treated
individuals. The lipid coating of this disclosure provides a
significant barrier to moisture, humidity and exposure to light by
allowing for a physical barrier as well as one that prevents and/or
reduces hydrolysis. The coated enzyme preparations undergo less
hydrolysis as a result of protection from moisture in the
environment by the lipid coating. As a result of the present
disclosure, pancreatic/digestive enzymes are provided which can
tolerate storage conditions (e.g., moisture, heat, oxygen, etc.)
for long periods of time thus enabling extended shelf life. The
coating of the encapsulated enzyme preparation protects the enzyme
from the environment and provides emulsification in a solvent
without detracting from the abrasion resistance of the coating. The
disclosure thus further relates to more stable enzyme
preparations.
[0092] It is another aspect of the present disclosure to make an
enzyme preparation without the use of extenders colorants, dyes,
flow enhancers and other additives to reduce the potential for
allergens and other sensitivity reactions in children and other
treated individuals. It has been discovered that in some
embodiments, the digestive enzymes can be encapsulated with a
single lipid excipient to improve retention of enzyme activity,
ease of administration, tolerability, and safety of administration,
among other properties. Surprisingly, digestive enzyme particles
containing lipases can be successfully encapsulated with coating
consisting essentially of only hydrogenated soy oil.
[0093] Porcine pancreatic/digestive enzymes possess a significant
odor and taste, similar to cured or smoked pork. This taste and
smell can be strong and offensive to some individuals taking enzyme
replacement, and especially to children. In one embodiment, the
addition of a lipid coating provides significant odor and taste
masking to the enzyme preparation, which allows for the tolerance
of taste, as the lipid coating is odorless and tasteless. The use
of this method of taste masking not involving the use of color,
dyes, perfumes or other substances is preferable for the
administration of medications, which have an unpleasant or
undesirable taste and odor. In another embodiment, this disclosure
relates to coated digestive enzyme preparations with improved taste
and odor.
[0094] In some embodiments, the coatings on the digestive enzyme
particle cores are preferably continuous coatings. By "continuous",
it is meant that the pancreatic/digestive enzyme is completely
surrounded. The continuous coating fully surrounds or encapsulates
the pancreatic/digestive enzymes. The encapsulation provides
protection of the pancreatic/digestive enzyme from conditions such
as moisture and oxidation.
[0095] In the manufacture of pharmaceuticals, encapsulation refers
to a range of techniques used to enclose medicines in a relatively
stable shell known as a capsule, allowing them to, for example, be
taken orally or be used as suppositories. "Encapsulate" as used
herein means that the coating completely surrounds the
pancreatic/digestive enzyme. A coated or encapsulated preparation
may contain one or more digestive enzyme particles enveloped in one
coating to form one coated or encapsulated digestive enzyme
particle in the coated or encapsulated digestive enzyme
preparation.
[0096] The two main types of capsules are hard-shelled capsules,
which are normally used for dry, powdered ingredients, and
soft-shelled capsules, primarily used for oils and for active
ingredients that are dissolved or suspended in oil. Both of these
classes of capsule are made both from gelatin and from plant-based
gelling substances like carrageenans and modified forms of starch
and cellulose, and the latter form is usually seamless. Capsules
are made in two parts by dipping metal rods in molten gelatin
solution. The capsules are supplied as closed units to the
pharmaceutical manufacturer. Before use, the two halves are
separated, the capsule is filled with powder (either by placing a
compressed slug of powder into one half of the capsule, or by
filling one half of the capsule with loose powder) and the other
half of the capsule is pressed on. The advantage of inserting a
slug of compressed powder is that control of weight variation is
better, but the machinery involved is more complex.
[0097] Sprinkle capsules are a dosage form consisting of small
beads or granules of an active drug contained in a capsule that can
be readily administered by simply opening up the capsule and
distributing the contents over something to be swallowed.
[0098] In addition, the encapsulation also provides controlled
release of the pancreatic/digestive enzyme. In one embodiment, the
emulsification properties of the coating in a solvent allows for
controlled release of the enzyme in the gastrointestinal (GI)
system, preferably the region of the GI tract where the enzymes are
to be utilized. For example, for conditions requiring treatment
with proteases, the release of the protease portion of the enzymes
is necessary in the proximal small intestine, thereby necessitating
a lipid encapsulation, which has a dissolution profile showing a
release of between 10% to 100% of the active substance into
solution over a time period of between 30 and 90 minutes. In one
embodiment, the dissolution profile shows a release of about 20%,
30%, 40%, 50%, 60%, 70%, 80%, 90% or 100%, and all values in
between, of the coated substance into solution over a time period
of about 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85 or 90
minutes and all values in between. Dissolution profiles may be
obtained using methods and conditions known to those of skill in
the art. For example, dissolution profiles can be determined at
various pHs, including pH 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 and all
values in between.
[0099] The rate of release of the bioactive substance can also be
controlled by the addition of additives as described below. When
the preparations are exposed to a solvent, the solvent interacts
with the mollifiable lipid in the coating and results in
emulsification of the coating and release of the bioactive
substance.
[0100] A suspension is a heterogeneous fluid containing solid
particles that are sufficiently large for sedimentation. Usually
they must be larger than 1 micrometer. The internal phase (solid)
is dispersed throughout the external phase (fluid) through
mechanical agitation, with the use of certain excipients or
suspending agents. Unlike colloids, suspensions will eventually
settle. An example of a suspension would be sand in water. The
suspended particles are visible under a microscope and will settle
over time if left undisturbed. This distinguishes a suspension from
a colloid in which the suspended particles are smaller and do not
settle. Colloids and suspensions are different from a solution, in
which the dissolved substance (solute) does not exist as a solid
and solvent and solute are homogeneously mixed. Oftentimes, powders
of active ingredients may be packaged such that the addition of a
diluent dissolves the powder and holds it in a liquid
suspension.
[0101] A pharmaceutical preparation may be prepared in which an
excipient provides a matrix to capture and protect a product before
delivery. Pharmaceutical preparations may be prepared whereby the
individual who takes the preparation has a reduction in the number
of capsules/tablets per dosage; i.e., the preparation is stabilized
and may contain a therapeutically effective amount of a protease,
an amylase, and/or a lipase. Preparations may include, for example,
a stabilizing matrix consisting essentially of a solidified
microcrystalline cellulose which captures and protects
therapeutically effective amounts of digestive enzyme particles
within the stabilizing matrix. This can be done, for example,
through the use of what is known in the art as Prosolv.RTM.
technology.
[0102] Prosolv.RTM. is a combination of excipients which allow for
optimized flow, compaction and product uniformity. This technology
allows for uniformity in this combination, as well as manufacturing
a very small tablet which would be amenable for children. With
Prosolv.RTM. technology, the ingredients are not just blended, but
are co-processed, which assures that equal particles are uniformly
distributed and these results are easily reproducible. This allows
for stability and superb product quality.
[0103] Whether utilizing the Prosolv.RTM. method or other
methodology, the one or more digestive enzymes will be formulated
and manufactured such that the particles will be uniformly
distributed and there will be no overage with respect to the amount
of enzyme found in the preparation. Said new drug formulation can
be found in, but is not limited to, formulations which include
digestive/pancreatic enzymes with and without the utilization of
the Prosolv.RTM. technology.
[0104] In a further embodiment, a direct compression method may be
used for the manufacture of a pharmaceutical tablet preparation
including the steps of: (a) forming an active blend by blending an
intimate admixture of silicified microcrystalline cellulose and a
therapeutic agent comprising one or more digestive enzymes; (b)
forming a color blend by blending an intimate admixture of one or
more pharmaceutically acceptable dyes and silicified
microcrystalline cellulose if color is necessary; (c) combining the
active blend, the color blend and a disintegrant into a pre-blend;
(d) adding a lubricant to the pre-blend to form a final blend; and
(e) compressing the final blend to form a pharmaceutical tablet
preparation or a mixture of time released microtabs or a time
released tablet.
[0105] This may be accomplished by combining the digestive enzymes
with one of the patented Prosolv.RTM. technologies, i.e.:
Prosolv.RTM. SMCC 50 or Prosolv.RTM. SMCC 90, or other Prosolv.RTM.
technologies. When employing the Prosolv.RTM. method, the
silicified microcrystalline cellulose (SMCC) used in the
preparation of the present invention may be any commercially
available combination of microcrystalline cellulose granulated with
colloidal silicon dioxide. The SMCC generally will be as described
in Sherwood et al, Pharm. Tech., October 1998, 78-88 and U.S. Pat.
No. 5,585,115, which is incorporated herein by reference in its
entirety. SMCC can be obtained commercially from Edward Mendell
Company, Inc., a subsidiary of Penwest Ltd., under the name
ProSolv.RTM. SMCC. There are different grades of SMCC available,
with particle size being the differentiating property among the
grades. For example, ProSolv.RTM. SMCC 90 has a median particle
size, by sieve analysis, in the region of 90 micrometers.
ProSolv.RTM. SMCC 50 has a median particle size, by sieve analysis,
in the region of about 40-50 micrometers.
[0106] A pharmaceutical composition described herein may be
prepared using a direct compression method, a dry granulation
method, or by wet granulation. Preferably, the digestive/pancreatic
enzyme preparation may be prepared using a direct compression
process. This preferred process consists of two main steps:
blending and compression.
[0107] The blending step is composed of an active blend, color
blend, pre-blend, and final blend (lubrication). The formulation of
the present invention may include a number of other ingredients for
optimal characteristics of the pharmaceutical composition. Such
other ingredients and the amounts to be used are within the
knowledge of one in the art and are known in the pharmaceutical
arts. These may include disintegrates, lubricants and/or coloring
agents among others. Suitable disintegrants include, for example,
sodium starch glycolate, other starches such as pregelatinized
starch, and celluloses. Suitable lubricants may be provided, such
as magnesium stearate, calcium stearate, talc and stearic acid. Any
coloring agent certified by the FDA may be used, such as FD&C
Yellow #6, among others.
[0108] When used as a pharmaceutical preparation, elixirs contain
an active ingredient that is dissolved in a solution that contains
some percentage (usually 40-60%) of ethyl alcohol and is designed
to be taken orally.
[0109] Syrups are oftentimes employed as a base for medicinal
purposes and consist of a concentrated or saturated solution of
refined sugar in distilled water.
[0110] A suspension of liquid droplets or fine solid particles in a
gas is called an aerosol. This can take the form of an oral
spray.
[0111] A gum may be devised whereby an active ingredient is
incorporated into a vegetative resinous substance (e.g. acacia) and
released via the actual mechanical effect of chewing or the action
of saliva on the gum itself.
[0112] A thinstrip is an active pharmaceutical product coated by a
lipid layer designed to dissolve in the mouth over a brief period
of time. The same technology could be used to produce a medicated
lollipop for transmucosal delivery.
[0113] In pharmaceutical terms, a granule is a small particle
gathered into a larger, permanent aggregate in which the original
particles can still be identified.
[0114] In some aspects, the disclosure relates to the production of
selected coated enzyme preparations made by coating digestive
enzyme particles with lipids not previously used in coated
digestive enzyme preparations. The unique mixtures of emulsifiable
lipids and enzymes can deliver certain components of the
pancreatic/digestive enzymes to selected locations and/or at
selected times during transit of the GI tract. In some aspects, the
disclosure relates to methods of delivering digestive enzymes to
humans based upon dissolution profiles.
[0115] The emulsifiable lipid may be any lipid, lipid mixture, or
blend of lipid and emulsifiers which emulsifies when exposed to a
solvent, and has a melting point which allows the lipid to be a
solid at typical storage temperatures. The emulsifiable lipid can
be a vegetable or animal derived-lipid. In another embodiment, the
emulsifiable lipid consists essentially of, or comprises one or
more monoglycerides, diglycerides or triglycerides, or other
components including, for example, emulsifiers found in
hydrogenated vegetable oils. In another embodiment the lipid is a
non-polar lipid.
[0116] As used herein, animal and/or vegetable "derived" lipids can
include fats and oils originating from plant or animal sources
and/or tissues, and/or synthetically produced based on the
structures of fats and oils originating from plant or animal
sources. Lipid material may be refined, extracted or purified by
known chemical or mechanical processes. The lipid may, in one
embodiment, comprise a Type I USP-National Formulary vegetable
oil.
[0117] The digestive enzyme used in the present disclosure can be
any combination of digestive enzymes of a type produced by the
pancreas, including, but not limited to digestive enzymes from a
pancreatic source or other sources. The scope of the disclosure is
not limited to pancreatic enzymes of porcine origin, but can be of
other animal or plant origin as well as those that are
synthetically derived. In one embodiment, the digestive enzyme is
derived from mammalian sources such as porcine-derived digestive
enzymes. In another embodiment, the enzyme includes one or more
enzymes, and is plant derived, synthetically derived, recombinantly
produced in microbial, yeast, or mammalian cells, or includes a
mixture of enzymes from one or more sources. For example, digestive
enzymes may include one or more enzymes from one or more sources
mixed together. This includes, for example, the addition of single
digestive enzymes to digestive enzymes derived from pancreatic
sources in order to provide appropriate levels of specific enzymes
that provide more effective treatment for a selected disease or
condition. One source of digestive enzymes can be obtained, for
example, from Scientific Protein Laboratories. In one embodiment,
the digestive enzyme is, for example a pancreatin/pancrelipase
composition. In another embodiment, the digestive enzymes comprise
or consist essentially of 25 USP units protease, 2 USP units
lipase, and 25 USP units amylase per milligram. The term digestive
enzyme may refer to one or more enzymes of a type produced by the
pancreas.
[0118] In one embodiment, the digestive enzyme used present as
consisting of particles having various sizes. In another
embodiment, the particles of digestive enzyme are screened to
obtain particles of a suitable size for encapsulation by removing
particles that are too fine or too large. For example, the
particles may be sieved to obtain particles of a suitable size or
more uniform size range for encapsulation.
[0119] In one embodiment, the minimum amount of pancreatic enzyme
present in the core is at least about 5% active enzymes by weight
of the coated enzyme preparation, but in another embodiment is at
least about 30%, or at least about 50% by weight. In one
embodiment, the maximum amount of pancreatic/digestive enzyme
present in the composite is at most about 99% by weight, and in
another embodiment is at most about 98%, 95%, 90%, 85%, 80%, 75% or
70% of the coated enzyme preparation. In another embodiment, the
amount of pancreatic enzyme present in the composite is about 10%,
15%, 20%, 25%, 35%, 40%, 45%, 55%, 60%, 65%, 70%, 72.5%, 75%,
77.5%, 80%, 82.5%, 87.5%, or 92.5% by weight or anywhere in
between. At least about or at most about a % of enzyme may include
equal to or about that % of enzyme. The term "about" includes equal
to, and a range that takes into account experimental error in a
given measurement. As used in connection with particle sizes, the
term "about" can refer to plus or minus 10, 9, 8, 7, 6, 5, 4, 3, 2
or 1% or anywhere in between. As used in connection with %
particles that can be sieved, the term "about" can refer to plus or
minus 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1% or anywhere in between.
[0120] In one embodiment, the composition which contains the
encapsulated digestive enzyme preparation or composite is delivered
as a sprinkle, powder, capsule, tablet, pellet, caplet or other
oral form. In another embodiment, packaging the encapsulated enzyme
preparations in an enzyme delivery system that further comprises
single dose sachet-housed sprinkle preparations allows for ease of
delivery and accurate dosing of the enzyme by allowing a specific
amount of enzyme to be delivered in each dosing. Allowing for
specific unit dosing of an enzyme preparation which maintains the
enzyme activity within specific stability parameters is an
enhancement over other sprinkle formulations, which are housed in a
multi-unit dosing form that allows for air, moisture and heat to
depredate and denature the enzyme preparation. In one embodiment,
the powder or sachet is housed in a trilaminar pouch of which one
layer is foil, or similar barrier to keep out moisture and to
protect the enzyme preparation from adverse environmental factors.
The disclosure further relates to an improvement in stability due
to a reduction in hydrolysis due to the lipid encapsulation and
composition of package.
[0121] In another embodiment, the lipid encapsulation methodology
reduces the aerosolization of the enzyme preparation that may be
caustic to the patient if inhaled. In another embodiment, the
disclosure includes delivery of digestive enzymes with improved
safety of administration, by reducing the amount of aerosolization
of the enzyme. The lipid encapsulation reduces aerosolization and
the potential for caustic burn, aspiration, and/or aspiration
pneumonias in patients and administrators of the enzyme
preparation, thereby reducing the potential for illness in already
compromised children such as those with cystic fibrosis, and
leading to safer administration.
[0122] As used herein, the term "non-aerosolizable" will be used to
refer to a coated or encapsulated enzyme preparation where
substantially all of the particles are large enough to eliminate or
reduce aerosolization upon pouring of the coated enzyme preparation
compared to uncoated enzyme particles.
[0123] As described and referred to herein, suitable
pancreatic/digestive enzymes and suitable coatings may be used in
the compositions and methods of this disclosure. The choice of
suitable enzymes and of suitable lipid coatings, including choice
of the type or amount of enzymes or coating, are guided by the
specific enzyme needs of the individuals, and the selected diseases
to be treated. The encapsulated enzyme preparations that are one
aspect of this disclosure have not been previously described.
[0124] In another embodiment, the disclosure relates to a method of
controlling the rate of release of the pancreatic/digestive enzyme
from an encapsulated enzyme preparation upon exposure to a solvent.
In one aspect, the method comprises blending an emulsifiable lipid
with an amount of one or more additives to obtain a lipid blend and
coating the digestive enzyme particle with the blend to form an
encapsulated digestive enzyme preparation containing particles
comprising a core which contains the enzyme, and a coating which
contains the lipid. In one embodiment, the emulsifiable lipid is a
blend where the emulsifiable lipid and additive are not the same,
and where the rate of release of the enzyme from the encapsulated
composite upon exposure to a solvent is decreased as the amount of
additive is increased. In the alternative, the rate of release of
the enzyme from the encapsulated composite upon exposure to a
solvent is increased as the amount of additive is decreased.
[0125] The lipid coating surprisingly does not appear to be reduced
or destroyed by hydrochloric acid (HCl) present in the stomach,
thereby protecting the enzyme from degradation following
administration until the enzyme preparation reaches its target
region in the GI tract. Further the lipid coat reduces the exposure
of the enzyme to attack by water, thereby reducing hydrolysis, and
further protecting the digestive enzymes from degradation. In
addition, the inventors have found that an excipient containing
only lipid can be used to coat or encapsulate digestive enzyme
particles containing lipase.
[0126] Enzyme preparations supplied by the API supplier may be
provided as irregular shaped, and multi-sized particles, with
uneven edges, and much clumping, and containing some crystalline
salt particles. Uneven particle size and shape reduces flow
properties, and interferes with packaging. In addition, pouring
uncoated enzyme into the mouth of an individual would be difficult,
and potentially may cause too much or too little of the enzyme to
be delivered. In one embodiment, processing the digestive enzyme
particles according to methods in accordance with one aspect of
this disclosure yields a non-dusty, free-flowing particulate
preparation suitable for sachet packaging and for pouring onto food
or drink. In addition, as discussed throughout, the use of lipid
encapsulation to prevent aerosolization and, therefore, increase
safety, and to increase flow properties which enhance manufacturing
of a pharmaceutical is an embodiment of the instant disclosure.
[0127] "Emulsifiable lipids" as used herein means those lipids that
contain at least one hydrophilic group and at least one hydrophobic
group, and have a structure capable of forming a hydrophilic and
hydrophobic interface. These chemical and/or physical properties,
mentioned above of an emulsifiable lipid permit emulsification.
Examples of interfaces include, for example, micelles and bilayers.
The hydrophilic group can be a polar group and can be charged or
uncharged.
[0128] In one embodiment, the emulsifiable lipid is derived from
animal or vegetable origins, such as, for example, palm kernel oil,
soybean oil, cottonseed oil, canola oil, and poultry fat, including
hydrogenated type I vegetable oils. In one embodiment, the lipid is
hydrogenated. In another embodiment, the lipid is saturated or
partially saturated. Examples of emulsifiable lipids include, but
are not limited to, monoglycerides, diglycerides, fatty acids,
esters of fatty acids, phospholipids, salts thereof, and
combinations thereof.
[0129] The emulsifiable lipid is preferably a food grade
emulsifiable lipid. Some examples of food grade emulsifiable lipids
include sorbitan monostearates, sorbitan tristearates and calcium
stearoyl lactylates. Examples of food grade fatty acid esters which
are emulsifiable lipids include acetic acid esters of mono- and
diglycerides, citric acid esters of mono- and di-glycerides, lactic
acid esters of mono- and digylcerides, polyglycerol esters of fatty
acids, propylene glycol esters of fatty acids, and diacetyl
tartaric acid esters of mono- and diglycerides. Lipids can include,
for example, hydrogenated soy oil. Any emulsifiable lipid may be
used in the methods and products of this disclosure. In one
embodiment, the emulsifiable lipid used will produce
non-agglomerating, non-aerosolizing enzyme preparation
particles.
[0130] In another embodiment, the method relates to preparation of
an encapsulated, controlled release digestive enzyme preparation
with enhanced flow properties useful in the treatment of
individuals with a neurological or neuropsychiatric disorder, the
method comprising: a) blending an emulsifiable lipid with one or
more additives to obtain a blend; and b) coating screened digestive
enzyme with the blend to form an encapsulated digestive enzyme
containing a core which contains the digestive enzyme and a coating
which contains the blend of emulsifiable lipid.
[0131] The coating of the enzyme with the lipid allows for the
enzyme to become more uniform in size and shape, but reduces the
jagged edges associated with the raw enzyme, and allows for ease of
administration and ease of packaging, as the flow properties
associated with the covered enzyme will allow for the packaging
machinery to easily fill the sachet/pouch with the enzyme and
reduces overfilling or underfilling of the sachet.
[0132] In another embodiment, the disclosure relates to a method of
controlling the rate of release of a digestive enzyme from the
encapsulated preparation by using a lipid blend to coat the
digestive enzyme. The method includes blending an emulsifiable
lipid with one or more additives to obtain a blend, and coating the
digestive enzyme with the blend to form an encapsulated digestive
enzyme containing a core which contains the digestive enzyme and a
coating which contains the blend of emulsifiable lipid. The rate of
release of the enzyme from the encapsulated preparation upon
exposure with a solvent is decreased as the amount of additive is
increased. In the alternative, the rate of release of the enzyme
from the encapsulated composite upon exposure with a solvent is
increased as the amount of additive is decreased. Thus, the nature
of the coating allows for controlled release of the enzyme from the
encapsulate.
[0133] Different dosage forms have different benefits. Tablets and
capsules are the most common dosage forms for oral administration
due to ease of manufacture, packaging and administration. Different
forms of tablets have been primarily devised to meet the needs of
select populations while maintaining the integrity of the active
pharmaceutical ingredient. Some populations, notably infants and
young children, cannot swallow tablets or capsules or find it
difficult to do so. In these instances, a tablet that dissolves
under the tongue, in the mouth, or in a specified liquid, or one
that could be harmlessly chewed would be beneficial. Capsules that
could be opened and their contents sprinkled over a small amount of
food or in a liquid would also be beneficial. Any improvement that
eases the administration of a necessary medication or lessens the
antagonism associated with said administration, without
compromising the effectiveness of the active pharmaceutical
ingredient, is worthwhile.
[0134] Other types of solid dosage forms such as thin strips,
lollipops or gum bring a novel concept to the administration of
medications to children. Aside from the obvious ease of
administration from the viewpoint of the caregiver, there may be an
added benefit. The administration of medication is oftentimes a
private issue and the ability of a caregiver to provide a dose of
medication in a seemingly matter-of-fact form may preserve that
perception and instill in the user a mindset that views the
administration as pleasant rather than monotonous or negative.
[0135] Liquid dosage forms also provide benefits of administration
to infants and young children or anyone with compromised swallowing
capability. Syrups, solutions and suspensions are easily swallowed.
Unpleasant tastes can be masked by flavoring. An oral spray allows
for the quick administration of a pre-measured dose of medication
and supplies multiple metered doses in one handy device. With no
need to aid swallowing (such as a glass of water, etc.) and the
convenience of not having to rifle through a bottle of tablets,
administration is simplified.
[0136] A tablet is a mixture of active substances and excipients,
usually in powder form, pressed or compacted into a solid. The
excipients include binders, glidants (flow aids) and lubricants to
ensure efficient tableting; disintegrants to ensure that the tablet
breaks up in the digestive tract; sweeteners or flavors to mask the
taste of bad-tasting active ingredients; and pigments to make
uncoated tablets visually attractive. A coating (sugar, enteric or
film) may be applied to hide the taste of the tablet's components,
to make the tablet smoother and easier to swallow, and to make it
more resistant to the environment, extending its shelf life.
Tablets may be buffered (by potassium metaphosphate, potassium
phosphate, monobasic sodium acetate, etc.) to combat change in pH.
Tablets may be delayed-release, sustained-release,
extended-release, controlled-delivery, long-acting,
orally-disintegrating or melts, among others, often denoting the
pharmacokinetic profile of the active agent. A capsule-shaped
tablet is a caplet.
[0137] Some tablets may be taken sublingually or allowed to
dissolve in the mouth. The principle behind sublingual
administration is simple. When a chemical comes in contact with the
mucous membrane beneath the tongue, or buccal mucosa, it diffuses
through it. Because the connective tissue beneath the epithelium
contains a profusion of capillaries, the substance then diffuses
into them and enters the venous circulation. Troches are medicated
lozenges designed to dissolve in the mouth. Soluble tablets
dissolve on contact with the tongue.
[0138] Slurry may be made when a dissolvable tablet containing a
gelling agent is added to a liquid.
[0139] Tablets may also be micro-coated and placed in a capsule for
administration.
[0140] The compositions described herein can be administered either
alone or more typically in combination with one or more of a
conventional pharmaceutical carrier, excipient buffer, stabilizer
or the like. Such materials should be non-toxic and should not
interfere with the efficacy of the active ingredient. The precise
nature of the carrier or other material will depend on the route of
administration. The term "excipient" is used herein to describe any
ingredient other than the compound(s) (enzymes) used in the
composition as described herein and known in the art.
[0141] Acceptable carriers are physiologically acceptable to the
administered patient and retain the therapeutic properties of the
compounds with/in which it is administered. Acceptable carriers and
their formulations are and generally described in, for example,
Remington' pharmaceutical Sciences (18th Edition, ed. A. Gennaro,
Mack Publishing Co., Easton, Pa. 1990). Two exemplary carriers are
water and physiological saline. The phrase "pharmaceutically
acceptable carrier" as used herein means a pharmaceutically
acceptable material, composition or vehicle, such as a liquid or
solid filler, diluent, excipient, solvent or encapsulating
material, involved in carrying or transporting the subject
compounds from the administration site to a portion of the body.
Each carrier is acceptable in the sense of being compatible with
the other ingredients of the formulation and not injurious to a
subject to whom it is administered. Nor should an acceptable
carrier alter the specific activity of the subject compounds.
[0142] Acceptable carriers, excipients, or stabilizers are those
that are non-toxic to recipients at the dosages and concentrations
employed, and include buffers such as phosphate, citrate, and other
organic acids; antioxidants including ascorbic acid and methionine;
preservatives (such as octadecyldimethylbenzyl ammonium chloride;
hexamethonium chloride; benzalkonium chloride, benzethonium
chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as
methyl or propyl paraben; catechol; resorcinol; cyclohexanol;
3-pentanol; and m-cresol); low molecular weight (less than about 10
residues) polypeptides; proteins, such as serum albumin, gelatin,
or immunoglobulins; hydrophilic polymers such as
polyvinylpyrrolidone; amino acids such as glycine, glutamine,
asparagine, histidine, arginine, or lysine; monosaccharides,
disaccharides, and other carbohydrates including glucose, mannose,
or dextrins; chelating agents such as EDTA; sugars such as sucrose,
mannitol, trehalose or sorbitol; salt-forming counter-ions such as
sodium; and/or non-ionic surfactants such as TWEEN.RTM.,
PLURONICS.RTM. or polyethylene glycol (PEG).
[0143] The phrase "pharmaceutically acceptable" refers to molecular
entities and compositions that are physiologically tolerable and do
not typically produce an allergic or similar untoward reaction,
such as gastric upset, dizziness and the like, when administered to
a human.
Dosing, Administration and Methods
[0144] Methods of preparing such dosage forms are known, or will be
apparent, to those skilled in this art; for example, see Remington:
The Science and Practice of Pharmacy, 21st Edition (Lippincott
Williams & Wilkins. 2005). Appropriate dosages will depend on
the patient (age, weight, overall health, etc.), the severity of
the condition, the type of formulation and other factors known to
those having ordinary skill in the art. It is to be noted that
concentrations and dosage values can vary with the severity of the
condition. It is to be further understood that for any particular
patient, specific dosage regimens should be adjusted over time
according to the individual need and the professional judgment of
the person administering or supervising the administration of the
compositions.
[0145] In one embodiment a composition can be administered 1 or
more times a day, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 times a
day with or without food. In another embodiment, a composition can
be administered orally 3 times a day with or without food.
[0146] The term "unit dose" when used in reference to a therapeutic
composition refers to physically discrete units suitable as unitary
dosage for humans, each unit containing a predetermined quantity of
active material calculated to produce the desired therapeutic
effect in association with the required diluent; i.e., carrier, or
vehicle.
[0147] Provided herein are methods for administering the enzyme
compositions/preparations. In one aspect, the methods include
administering the pancreatic/digestive enzymes as coated
preparations. In another aspect, the disclosure relates to a method
of treatment comprising administering to a subject with a
neurological or neuropsychiatric disorder, including but not
limited to: Adjustment disorders, addiction, Alzheimer's disease,
Anxiety disorders, Bipolar disorder, cognitive disorders,
dementias, Dissociative disorders, eating disorders,
Impulse-control disorders, Mood disorders, sexual disorders, sleep
disorders, psychotic disorders such as schizophrenic disorders
(e.g., schizophrenia), Somatoform disorders, substance abuse
disorders and personality disorders, or other behavioral or
neurological condition in need of treatment with digestive enzymes,
at least two doses of a composition comprising a therapeutically
effective amount of a coated or uncoated digestive enzyme
preparation comprising a core comprising a digestive enzyme.
Determination of whether a subject is in need of treatment with an
effective amount of digestive enzymes may be based on a
determination that the subject has an enzyme deficiency.
[0148] In one aspect of the present disclosure, it is well known
that determining a dosage regimen of the compound is well within
the purview of those in the art. By way of example, the dose levels
may range from 100 milligrams to 10 grams as determined by weight.
Further activity of the enzymes may range from 100 units of
activity to 1,500,000 units of activity per dose for amylases,
lipases and proteases, respectively.
[0149] In another embodiment, the disclosure relates to methods of
treatment comprising administering to a subject with a neurological
or neuropsychiatric condition susceptible to treatment with
digestive enzymes, at least two doses of a composition comprising a
therapeutically effective amount of the coated digestive enzyme
preparations. In certain embodiments, about 80% of the enzyme is
released by about 30 minutes in a dissolution test performed at pH
6.0. In other embodiments, about 80% of the enzyme is released by
about 30 minutes after the coated digestive enzyme preparations
reach the small intestine.
[0150] The disclosure further relates in another aspect to the
delivery of digestive enzymes with improved safety of
administration. The lipid coat adds weight to the enzyme
preparation, which reduces the potential for aerosolization.
Previous uncoated enzymes have been shown to become aerosolized,
and can therefore be inhaled and contact the nasal cavity or the
lungs, causing injury to the mucosa of those taking and those
administering the enzyme preparation.
[0151] The disclosure further relates to the improvement of
administering a sachet preparation for delivery to children. The
disclosure specifically relates to the administration of a coated
or uncoated digestive enzyme preparation, housed in a sachet which
allows for particular types of administration including but not
limited to administration in food, drink, or direct administration
into the oral cavity or directly into the GI system through a
NG-tube, G-tube or other GI entrances. The use of a sachet delivery
of enzymes has heretofore not been utilized in the enzyme
preparations presently marketed. In one embodiment, the sachet
represents a single unit dosage or multiple doses for a day. The
sachet of a trilaminar pouch allows the enzyme or enzyme/lipid
powder to remain stable, and allows for ease of administration.
[0152] The disclosure further relates to the administering of the
coated or uncoated enzyme preparation in a sachet or pouch
preparation for ease of delivery to children and adults. In some
embodiments, the disclosure specifically relates to the
administration of a coated or uncoated enzyme particle preparation,
housed in a sachet or pouch. This facilitates administration,
including but not limited to, administration in food or drink,
direct administration into the oral cavity, or administration
directly into the GI system through an NG-tube, G-tube or other GI
entrances or deliveries.
[0153] Compositions comprising an effective amount of the compound
may be administered via any conventional route including but not
limited to oral, parenteral, intramuscular, intravenous,
transmucosal, transdermal, suppository or other method. Further the
oral administration can be in the form of pellets, capsules,
caplets, beadlets, sprinkles, tablets, softgels or other
carrier.
[0154] The pharmaceutical formulations can also be prepared for
parenteral use. Such formulations typically take the form of
sterile isotonic solutions of the active ingredient according to
standard pharmaceutical practice.
[0155] In one embodiment of the present disclosure, the increase of
protein digestion of an individual suffering from a
neuropsychiatric disorder leads to the improvement of such
disorders. In another embodiment, an individual suffering from or
diagnosed with a neuropsychiatric disorder benefits from the
administration of digestive enzymes since digestive enzymes aid in
the protein digestion process. In one embodiment, the
neuropsychiatric symptoms of an individual suffering from or
diagnosed with the neuropsychiatric disorder is improved or
alleviated from the administration of digestive enzymes.
[0156] The present invention provides a method for using digestive
enzymes and their derivatives to alleviate the symptoms of
neuropsychiatric disorders. The method comprises administering to
the individual a digestive enzyme either naturally or recombinantly
derived, or their derivatives, in an amount effective to reduce the
symptoms of the neuropsychiatric disorder.
[0157] Provided herein are methods of preventing one or more
symptoms associated with a neuropsychiatric disorder by
administering a composition described herein. As used herein,
"prevention" refers to prophylaxis, prevention of onset of
symptoms, prevention of progression of a neuropsychiatric disorder.
As used herein, "inhibition", "prevention", "treatment" and
"treating" refer to, for example, stasis of symptoms, as well as
partial or full amelioration of one or more symptoms associated
with a neuropsychiatric disorder. The compositions described herein
may be used to minimize the developmental disruption associated
with schizophrenia. Patients may be assessed with respect to the
prodromal (pre-onset) phase of the illness, which can be detected
up to 30 months before the onset of symptoms. Administration of the
compositions may be used to limit or reduce the number of patients
who go on to develop schizophrenia, experience transient or
self-limiting psychotic symptoms and the non-specific symptoms of
social withdrawal, irritability, dysphoria, and clumsiness during
the prodromal phase.
[0158] Compositions can be administered to a patient in an amount
that is effective for producing some desired therapeutic effect by
alleviating one or more symptoms associated with a neuropsychiatric
disorder at a reasonable benefit/risk ratio applicable to any
medical treatment. A therapeutically effective amount is an amount
achieves at least partially a desired therapeutic or prophylactic
effect in tissue subject. The amount of digestive enzymes necessary
to bring about alleviation one or more symptoms associated with a
neuropsychiatric disorder is not fixed per se. The amount of
digestive enzymes administered may vary with the type of disorder,
extensiveness of the disorder, and size of the patient suffering
from the disorder. A response is achieved when the patient
experiences partial or total alleviation, or reduction of one or
more signs or symptoms of illness. The patient's symptoms can
remain static (i.e., not get worse) or can be reduced.
[0159] A physician can readily determine and prescribe the
effective amount (ED50) of the composition required. For example,
the physician could start doses of the compounds employed in the
composition at levels lower than that required in order to achieve
the desired therapeutic effect and gradually increase the dosage
until the desired effect is achieved. Alternatively, a dose can
remain constant.
[0160] In such methods of treatment, one or more symptoms are
ameliorated or reduced following administration of a composition
provided herein. In one embodiment, one or more symptoms of such
disorders are reduced in severity or duration by about 2%, about
5%, about 10%, about 15%, about 20%, about 25%, about 30%, about
35%, about 40%, about 45%, about 50%, about 55%, about 60%, about
65%, about 70%, about 75%, about 80%, about 90%, about 95%, or
about 100%. In another embodiment, one or more symptoms of such
disorders are reduced in severity or duration by about 2-fold,
about 5-fold, about 10-fold, about 15-fold, about 20-fold, about
25-fold, about 30-fold, about 35-fold, about 40-fold, about
45-fold, about 50-fold, about 55-fold, about 60-fold, about
65-fold, about 70-fold, about 75-fold, about 80-fold, about
90-fold, about 95-fold, about 100-fold or more.
[0161] The DSM IV Diagnostic Criteria for Schizophrenia may be used
to assess whether administration of a composition described herein
reduces the severity and/or duration of one or more symptoms of
schizophrenia.
[0162] In one embodiment, one or more characteristic symptoms are
reduced in severity and/or duration following administration of a
composition described herein. For example, two (or more) of the
following, each present for less than half or less than a quarter
of a 1-month period (or less if successfully treated): delusions,
hallucinations, disorganized speech (e.g., frequent derailment or
incoherence), grossly disorganized or catatonic behavior, negative
symptoms, i.e., affective flattening, alogia, or avolition.
[0163] In another embodiment, signs of social/occupational
dysfunction are improved following administration of a composition
described herein. That is, a patient may exhibit an improvement in
one or more major areas of functioning such as work, interpersonal
relations, or self-care.
[0164] In yet another embodiment, the duration of symptoms may be
reduced in severity and/or duration following administration of a
composition described herein. That is, continuous signs of
disturbance that meet Criterion A may persist for less than 6
months, 5 months, 4 months, 3 months, 2 months, 1 month, 3 weeks, 2
weeks or 1 week.
[0165] Another aspect provided herein is combination therapy of a
patient with a composition described herein along with another
therapeutically effective agent or rehabilitation.
[0166] In one embodiment, the one or more agents is an
antipsychotic medication. Exemplary antipsychotic medications are
dopamine antagonists and serotonin antagonists.
[0167] Examples of dopamine antagonists include, but are not
limited to: Acepromazine, Amisulpride, Amoxapine, Azaperone,
Benperidol, Bromopride, Butaclamol, clomipramine (mild),
chlorpromazine, chlorprothixene, clopenthixol, Clozapine,
domperidone, droperidol, eticlopride, flupenthixol, fluphenazine,
fluspirilene, haloperidol, iodobenzamide, loxapine, mesoridazine,
levomepromazine, metoclopramide, nafadotride, nemonapride,
Olanzapine, penfluridol, perazine, perphenazine, pimozide,
prochlorperazine, promazine, quetiapine, raclopride, remoxipride,
risperidone, piperone, spiroxatrine, stepholidine, sulpiride,
sultopride, tetrahydropalmatine, thiethylperazine, thioridazine,
thiothixene, tiapride, trifluoperazine, trifluperidol,
triflupromazine, and ziprasidone.
[0168] Examples of serotonin antagonists include, but are not
limited to: 5-HT3 antagonists, 5-HT2A receptor antagonists (e.g.,
ketanserin, which 5 HT2A, 5 HT2C and alpha 1 receptors).
[0169] In another embodiment, therapeutically effective
rehabilitation includes, but is not limited to, psychotherapy,
vocational rehabilitation, social rehabilitation, or a combination
thereof.
[0170] In another embodiment of the disclosure a transgenic mouse
as described by Ratty et.al (U.S. Pat. No. 5,723,719) and
incorporated herein by reference, is utilized to examine the
efficacy of the digestive enzyme preparation with respect to
administration of an effective amount of the enzyme and evaluating
the enzyme's effect on the circling phenotype of the transgenic
mouse.
[0171] The application of these enzymes of the high protease
classification as applied to the chakragati mouse represents a
novel discovery for the use of enzymes for neuropsychiatric
disorders.
[0172] In one embodiment, the digestive enzyme has an effect on the
circling behavior and thus on neuropsychiatric disorders including
such conditions as schizophrenia.
[0173] Studies with mouse models can effectively identify molecules
or compounds which may effectively change behaviors in humans. The
scale-up of such findings in mice is part of the traditional drug
development pathway.
[0174] The chakragati (ckr) mouse, the result of a transgenic
insertional mutation, exhibits an abnormal circling behavior in
response to environmental stress cues, such as cage banging.
Wild-type littermates and those that were heterozygous for the
transgene insertion did not exhibit this circling phenotype.
Analysis of the ckr mouse genome indicates genetic rearrangements
on mouse chromosome 16. A US patent was granted for the chakragati
mouse (U.S. Pat. No. 5,723,719).
[0175] Since its discovery, extensive genetic, pharmacological and
behavioral research has been carried out on the ckr mouse. The
research undertaken points to the utility of the ckr mouse as a
screening tool for neuropsychiatric drug discovery. Cerca Insights
Sdn Bhd has developed a cascade of assays, the ckr screen, to
characterize the properties of novel antipsychotic compounds. The
insights generated from the ckr screen may be used to enhance the
assessment of efficacy across the positive, negative and cognitive
domains of schizophrenia.
[0176] The endophenotypes that have been reported in the literature
with respect to the ckr mouse are as follows: Asymmetric
Up-regulation of Dopaminergic Tone, Circling, Hyperactivity,
Prepulse Inhibition Deficit, Latent Inhibition (LI), Social
Withdrawal, Lateral Ventricular Enlargement, Agenesis of the Corpus
Callosum, and Reduction of Myelinated Neurons in Striatum.
[0177] The human clinical manifestations of the above mouse
endophenotypes are as follows: Left hemi-spatial preference may be
linked to asymmetric striatal dopaminergic activity common to all
psychoses. A subgroup of schizophrenia patients has underlying
right striatal hyper-dopaminergia. There is a greater pathological
involvement of the dominant hemisphere in schizophrenia and of the
non-dominant hemisphere in bipolar disorder. (Lyon et al 1992;
Bracha 1989; Lohr & Caliguiri 1995)
[0178] Yet another human clinical manifestation of the above
endophenotypes: Left-prone circling behavior (neglect of
right-sided turning) was found in unmedicated schizophrenic
patients. A tendency was noted for circling to occur more
frequently among paranoid than nonparanoid schizophrenics. (Bracha
1987; Marder & Woods 1987)
[0179] Yet another human clinical manifestation of the above
endophenotypes: hyperactivation (reduced task-related suppression)
of default regions and hyperconnectivity of the default network may
contribute to disturbances of thought in schizophrenia and risk for
the illness. (Whitfield-Gabrelli et al 2009)
[0180] Yet another human clinical manifestation of the above
endophenotypes: impairment in prepulse inhibition (PPI) is
generally seen as sensorimotor deficits. PPI disruption occurs in
the prodromal stage of schizophrenia and in patients with
schizotypical personality disorder. (Quednow et al 2009; Kumari et
al 2008; Kunugi et al 2007)
[0181] In yet another human clinical manifestation of the above
endophenotypes: there is the absence of latent inhibition (LI) in
the acute phase of schizophrenia. LI is found to be correlated to
the duration of the disease. (Rascle et al 2001; Gray & Snowden
2005; Vaitl D et al 2002)
[0182] In yet another human clinical manifestation of the above
endophenotypes: longer duration of social withdrawal is evident in
untreated disease. (Schultz et al 2007; Iyer 2008; Hoffman
2007)
[0183] In yet another human clinical manifestation of the above
endophenotypes: ventricular enlargement represents a morphometric
endophenotype for schizophrenia. There is a significant correlation
between the size of the lateral ventricles and underestimation of
the metabolic activity of the caudate. (McDonald et al 2006;
Berkataki et al 2006; Reig et al 2007)
[0184] In yet another human clinical manifestation of the above
endophenotypes: reductions in the thickness of the anterior
callosum differentiate between high-risk individuals who transition
to psychosis and those who do not, which is highly predictive of
transition. (Walterfang et al 2008)
[0185] In yet another human clinical manifestation of the above
endophenotypes: myelin impairment is a key factor in the pathogenic
loop of psychiatric diseases and drug addiction. (Feng 2008)
[0186] The chakragati (ckr) mouse has been utilized as a model for
schizophrenia. Many "typical" and "atypical" antipsychotics have
been tested on this mouse model prior to, and subsequent to
approval in humans.
[0187] The circling phenotype exhibits a disruption in the
endogenous genetic locus affecting motor function, and the circling
behavior may represent an aberration associated with nigrostriatal
neurons of the brain. This may affect multiple pathways of
neurotransmission such as dopamine, adrenaline, noradrenaline,
serotonin or GABA.
[0188] The chakragati mouse is a unique and validated animal model
which tests "antipsychotic" potency of novel compounds. The mice
exhibit a persistent overactivity of the dopamine system caused by
a selective increase in striatal D.sub.2 receptor subtypes. In
general, antipsychotic medications are thought to reduce dopamine
overactivity by the following mechanisms: 1) stimulating dopamine
autoreceptors on dopamine neurons, thereby reducing functional
activity of the dopamine system and 2) blocking post-synaptic
dopamine receptors on dopaminoreceptive neurons or other
neurotransmitter systems secondary to dopaminoreceptive
neurons.
[0189] The chakragati (ckr) mouse has been proposed as a model of
aspects of schizophrenia. The mice, created serendipitously as a
result of transgenic insertional mutation, exhibit spontaneous
circling, hyperactivity, hypertone of the dopamine system, reduced
social interactions, enlarged lateral ventricles, deficits in
pre-pulse inhibition of acoustic startle and deficits in the latent
inhibition of conditioned learning, (Dawe et al 2010). In 2010 Dawe
et al studied the dose dependent effects of antipsychotic drugs
(haloperidol, pimozide, risperidone, clozapine, olanzapine,
ziprasidone, quetiapine and aripiprazole) on the spontaneous
hyperactivity of the mice. All the antipsychotic drugs tested
dose-dependently suppressed spontaneous hyperactivity.
Aripiprazole, which is known to be a dopamine D.sub.2 receptor
partial agonist, exhibited a tri-phasic dose-response, initially
suppressing hyperactivity at low doses, having little effect on
hyperactivity at intermediate doses, and suppressing activity again
at high doses. These data suggest that the spontaneous circling and
hyperactivity of the ckr mouse may allow screening of candidate
antipsychotic compounds, distinguishing compounds with
aripiprazole-like profiles.
[0190] Aripiprazole, (also known as ABILIFY.RTM.) is an
antipsychotic of a novel class acting as a partial and selective
dopamine agonist, produced a different pattern of change in
locomotor activity across doses. At lower doses (1.67-10 mg/kg) it
produced an apparently dose-dependent reduction in motor activity
followed by an increase in motor activity (15 mg/kg) and a
subsequent suppression of motor activity (30 mg/kg). It a may be
that this multiphasic pattern of change in motor activity across
doses reflects the dopamine receptor partial agonist activity of
aripiprazole. Thus, the nature of the dose-dependent response in
ckr mouse would be expected to differentiate a similar
dose-dependent pattern of motor disturbance but the low level of
basal activity in wild type mice would make this difficult to
detect. Even haloperidol, which is associated with far stronger
extrapyramidal motor side effects than aripiprazole, did not
produce a significant suppression in the locomotor activity of
control mice monitored during the dark cycle when they are most
active, (Neuroscience, Dawe et al 2010).
[0191] Administration of aripiprazole dose-dependently reduced the
locomotor activity of ckr mice (F6,54_4.626, P_0.001; FIG. 6B).
Post-hoc Dunnett's test comparisons with the vehicle control
revealed that doses of 3-10 mg/kg significantly reduced locomotor
activity. The response appeared to be multiphasic as a higher dose
of 15 mg/kg did not significantly suppress locomotor activity while
a higher still dose of 30 mg/kg again significantly suppressed
locomotor activity. Observationally, the dose of 30 mg/kg appeared
to be associated with marked overall suppression of motor function
suggestive of severe sedation. Although it was not possible to fit
the dose response curve function to the complete data set; it was
possible to fit a subset of the data describing the initial
suppression of activity at doses from 1.67 to 10 mg/kg with a curve
predicting an ED50 of 2.695 mg/kg (FIG. 6B). However, the responses
predicted by the function fitted failed to correlate with the
actual values observed (R2_0.811, P_0.189), (Dawe et al 2010).
[0192] Thus ckr mice homozygous for the transgene insertion show a
constellation of anatomical, biochemical and behavioral deficits
which resemble those often reported in schizophrenic patients, as
shown in the following Table. (Tones et al 2008).
TABLE-US-00001 Condition Schizophrenia Ckr Mice Aberrant Behaviors
Circling Behavior & Hyperactivity Yes Yes Sensorimotor Gating
Deficits Yes Yes Brain Pathologies Ventricular Enlargement Yes Yes
Myelination Abnormalities Yes Yes Metabolic Deficits Yes Yes
Response to Antipsychotics Clozapine and Olanzapine Yes Yes
Neurochemical Correlates Alterations in Dopamine Systems Yes Yes
Deficit is in Choline and N- Yes Yes acetylaspartate Typical Age of
Onset of Yes Yes** Pathology Early Adulthood Sex-Dependent
Prevalence of Disease *Human and mice share important genomic,
anatomical and physiological similarities. These similarities,
particularly in the genes involved in brain development, might
provide insight into disease pathogenesis. { . . . } **(Postnatal
Day 10 for onset of Aberrant Behaviors) (Torres 2008)
[0193] The validity of the ckr mouse mutant for understanding the
pathogenesis of schizophrenia is further supported in its ability
to respond to antipsychotic drug treatment. The most salient
endophenotype in the chakragati (ckr) mouse is its circling
behavior. Under conditions of subjective stress, the mutant mouse
shows consistent circling behavior with individual turns from 10 to
80 full body turns per minute. This behavior syndrome is also
characterized by lateral circling behavior (i.e. a left-preference
population bias), postural asymmetry and hyperactivity to sensory
stimuli. In this context drugs that block the N-Methyl-D-Aspartate
(NMDA) subtype of the glutamate receptor such as phencyclidine
(PCP, also known as angel dust) and ketamine (a dissociate
anesthetic), usually elicit a psychotic-like-state that resembles
schizophrenia in preclinical models of the disease. This
psychotic-like state includes aberrant behavior syndromes (i.e.
positive symptoms) similar to those listed for the ckr mouse. It
should be noted that atypical neuroleptics such as clozapine and
olanzapine (antipsychotic agents that selectively alleviate
symptoms of schizophrenia) also alleviate the lateralized circling
behavior and aberrant postural asymmetry exhibited by the ckr
mouse. (Torres et al 2008).
Examples
Example 1. Pancreatin
[0194] Pancreatin is a substance comprising enzymes, principally
amylase, lipase, and protease, obtained from the pancreas of the
hog, Sus scrofa Linne var. domesticus Gray (Fam. Suidae) or of the
ox, Bos taurus Linne (Fam. Bovidae). Pancreatin contains, in each
mg, not less than 25 USP units of amylase activity, not less than 2
USP units of lipase activity, and not less than 25 USP units of
protease activity. Pancreatin of a higher digestive power may be
labeled as a whole-number multiple of the three minimum activities
or may be diluted by admixture with lactose, or with sucrose
containing not more than 3.25 percent of starch, or with pancreatin
of lower digestive power.
Example 2. Pancrelipase
[0195] Pancrelipase is a substance containing enzymes, principally
lipase, with amylase and protease, obtained from the pancreas of
the hog, Sus scrofa Linne var. domesticus Gray (Fam. Suidae). It
contains, in each mg, not less than 24 USP Units of lipase
activity, and not less than 100 USP Units of amylase activity, and
not less than 100 USP Units of protease activity.
[0196] The drug substance, pancreatic enzyme concentrate (porcine
origin) is purchased from an appropriate supplier. The properties
of an exemplary pancreatic enzyme concentrate (pancreatin) suitable
for use in the products of this invention are described in the
table below.
TABLE-US-00002 Parameter USP Specification Protease (USP) NLT 25
USP units/dose Lipase (USP) NLT 2 USP units/dose Amylase (USP) NLT
25 USP units/dose Fat (USP) NMT 6.0%* Loss on Drying (USP) NMT 5.0%
Escherichia coli (USP) Neg/10 g Salmonella species (USP) Neg/10 g
*If less than 75 U/mg Protease, 6 U/mg Lipase or 75 U/mg Amylase,
then specification is NMT 3.0%
Example 3. Mouse Model Study I
[0197] Attenuation of hyperactivity in the ckr mouse has been shown
to be predictive of antipsychotic efficacy. By way of testing
digestive enzymes to determine their effect on the circling
behavior and hyperactivity of the ckr transgenic mouse, two
strengths of the enzyme CM100 were tested on the mouse. (FIG. 1).
CM100 was administered twice daily for 14 days.
[0198] Dosing of the ckr mouse was separated into two strengths: a
10 mg pancreatin suspended in 1 mL of water and a second dosage of
20 mg of pancreatin suspended in 1 mL of water. (FIG. 2). The
vehicle used was autoclaved reverse osmosis water. The dosage
regimen consisted of twice daily dosing for 14 days at 0800 hours
and 2000 hours. Oral gavage was the route of administration. A 20 G
autoclavable gavage needle was utilized, and the administration was
done at 0.1 ml/10 g BW. The methodology as described may be altered
accordingly as one skilled in the art of administration of enzymes
or administration via gavage methodology to mice. One ordinarily
skilled in the art would be able to administer the enzyme.
[0199] The instant disclosure is comprised of an enzyme preparation
comprised of amylases, proteases and lipases. Doses used had a
human equivalent strength of between 155,000 and 310,000 units of
protease activity, the main component of the enzyme preparation.
(FIG. 3)
[0200] Dosing of the ckr mouse commenced Day 1 and continued to Day
14. Dosing was conducted twice daily for 14 days, once in the
morning between 7 am and 8 am and once in the evening between 7 pm
and 8 pm (12 hours apart). The open field assays were conducted on
6 days: Day 1, Day 3, Day 7, Day 14, Day 15 and Day 18. Distance
moved was recorded in 10 min-bins during the 20 minutes monitoring
period. Results were compared to the data for the same parameters
for 10 minutes determined for untreated ckr mice in prior
experiments (n=54).
[0201] For the 20 mg/ml (high dose), one-way ANOVA showed
significant changes in distance moved, (F6,87=3.1713, p=0.0076).
Paired t-test showed significant differences in velocity between
UNTREATED/D1 (t=1.98969, p=0.0011)*, UNTREATED/D3 (t=1.98969,
p=0.0454)**, UNTREATED/D7, (t=1.98969, p=0.0157)** and
UNTREATED/D18, (t=1.98969, p=0.0203)**. Tukey-Kramer test showed
significance between UNTREATED/D1 with p<0.05.
[0202] 2-way ANOVA showed significant differences in distance moved
between low and high dose subjects across time (F1, 14=5.3582,
p=0.0363). Within the subjects of high and low dose, there are
significant differences across time (F5, 10=4.4951, p=0.0209).
[0203] For 20 mg/ml (high dose), one-way ANOVA showed significant
changes in velocity (F6,87=3.1984, p=0.0072). Paired t-test showed
significant differences in velocity between UNTREATED/D1
(t=1.98969, p=0.0009)*, UNTREATED/D3 (t=1.98969, p=0.0399)**,
UNTREATED/D7, (t=1.98969, p=0.0211)** and UNTREATED/D18,
(t=1.98969, p=0.0201)**.
Example 4. Mouse Model Study II
[0204] Dosing of the ckr mouse was separated into two strengths: a
10 mg pancreatin suspended in 1 mL of water and a second dosage of
20 mg of pancreatin suspended in 1 mL of water. (FIG. 2). The
vehicle used was autoclaved reverse osmosis water. The dosage
regimen consisted of twice daily dosing for 14 days at 0800 hours
and 2000 hours. Oral gavage was the route of administration. A 20 G
autoclavable gavage needle was utilized, and the administration was
done at 0.1 ml/10 g BW. The methodology as described may be altered
accordingly as one skilled in the art of administration of enzymes
or administration via gavage methodology to mice. One ordinarily
skilled in the art would be able to administer the enzyme.
[0205] The instant disclosure is comprised of an enzyme preparation
comprised of amylases, proteases and lipases. Doses used had a
human equivalent strength of between 155,000 and 310,000 units of
protease activity, the main component of the enzyme preparation.
(FIG. 3)
[0206] Dosing commenced Day 1 and continued to Day 14. Dosing was
conducted twice daily for 14 days, once in the morning between 7 am
and 8 am and once in the evening between 7 pm and 8 pm (12 hours
apart). The open field assays were conducted on 6 days: Day 1, Day
3, Day 7, Day 14, Day 15 and Day 18. Velocity was recorded in 10
min-bins during the 20 minute monitoring period. These were
compared to the data for the same parameters for 10 minutes
determined for untreated ckr mice in prior experiments (n=54).
[0207] For 20 mg/ml (high dose), one-way ANOVA showed significant
changes in velocity (F6,87=3.1984, p=0.0072). Paired t-test showed
significant differences in velocity between UNTREATED/D1
(t=1.98969, p=0.0009)*, UNTREATED/D3 (t=1.98969, p=0.0399)**,
UNTREATED/D7, (t=1.98969, p=0.0211)** and UNTREATED/D18,
(t=1.98969, p=0.0201).
[0208] Tukey-Kramer test showed significance between UNTREATED/D1
with p<0.05.
[0209] 2-way ANOVA showed significant differences in velocity
between low and high dose subjects across time (F1,14=5.0932,
p=0.0405). Within the subjects of high and low dose, there are
significant differences across time (F5, 10=4.6769, p=0.0184).
Example 5: Mouse Model Study III
[0210] Amphetamine-induced hyperactivity as a model of psychosis in
schizophrenia is well established in the industry. FIGS. 7 and 8
are two graphs that depict the results of administration of CM-182
at 30 mg/ml (i.e., approximately 465,000 units of protease) to mice
injected with amphetamine to induce hyperactivity and to mice
injected with saline as a control.
[0211] The dose significantly attenuated the amphetamine-induced
hyperactivity, noted as an insignificant difference between the two
groups of mice in total distance moved in FIG. 7 and in velocity in
FIG. 8. It was also observed that CM-182 did not affect baseline
activity in these mice, suggesting that the attenuation of
hyperactivity occurred in a manner unrelated to sedation.
Essentially, the administered compound is non-sedating. What the
present inventors have identified is that significance exists
between the two of the groups in both graphs (but not in the 30
mg/ml group), suggesting that the amphetamine did indeed induce
hyperactivity to begin with.
[0212] While preferred embodiments have been shown and described
herein, such embodiments are provided by way of example only.
Numerous variations, changes and substitutions may occur without
departing from the disclosure. It should be understood that various
alternatives to the embodiments of the disclosure described herein
may be employed in practicing the disclosure. It is intended that
the following claims define the scope of the disclosure and that
methods and structures within the scope of these claims and their
equivalents be covered thereby.
* * * * *